Modulators of thr-beta and methods of use thereof

ABSTRACT

Disclosed herein are compounds of Formula I:TL-La-CE-HD  (I)or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 63/005,661, filed on Apr. 6, 2020, U.S.Provisional Patent Application Ser. No. 62/944,052, filed on Dec. 5,2019, and U.S. Provisional Patent Application Ser. No. 62/845,252, filedon May 8, 2019, the entire disclosure of each of which is herebyincorporated by reference herein.

FIELD OF THF INVENTION

The present invention is in the field of pharmaceutical compounds andpreparations and method of their use in the treatment of disease. Inparticular, the present invention is in the field of THR-β modulatorsand their use.

BACKGROUND OF THF DISCLOSURE

In parallel with the global increase in obesity, nonalcoholic fattyliver disease (NAFLD) is becoming the leading cause of chronic liverdisease and liver transplantation worldwide [1,2]. NAFLD is believed toaffect 30% of the adult population and 70-80% of individuals who areobese and diabetic. NAFLD is defined as excess liver fat accumulationgreater than 5% induced by causes other than alcohol intake. NAFLDprogresses to liver inflammation (nonalcoholic steatohepatitis, NASH)and fibrosis in a variable proportion of individuals, ultimately leadingto liver failure and hepatocellular carcinoma (HCC) in susceptibleindividuals [3].

In the United States alone, NASH is the third most common indication forliver transplantation and is on a trajectory to become the most common[4]. The most important medical need in patients with NAFLD and NASH isan effective treatment to halt the progression and possibly reversefibrosis, which is the main predictor of liver disease evolution [5,6].

Thyroid hormone (TH) is essential for normal development, growth andmetabolism of all vertebrates. Its effects are mediated principallythrough triiodothyronine (T3), which acts as a ligand for the THreceptors (TRs, or THRs) β1, β2 and α1 [7]. In the absence of ligand, TRfirst binds as a heterodimer or homodimer on TH response elements (TRE)located in the promoter regions of target genes, where it interacts withcorepressors. Upon ligand binding, the TR homodimers are dissociated infavor of heterodimer formation with the retinoid-X receptor (RXR),resulting in release of the corepressors and recruitment ofcoactivators. This new complex attracts a large number of proteins whichengage the RNA polymerase II in the transcription of the targeted genes.

Two different genetic loci, denoted THRA and THRB, are responsible forencoding multiple interrelated TR isoforms that have distinct tissuedistributions and biological functions. The two major isoforms with thebroadest level of tissue expression are TRα1 and TRβ1 [8]. While TRα1 isexpressed first during fetal development and is widely expressed inadult tissues, TRβ1 appears later in development and displays highestexpression in the adult liver, kidney, and lung [9]. TRα1 is a keyregulator of cardiac output, whereas TRβ1 helps in the control ofmetabolism in the liver. Importantly, the natural thyroid hormone T3activates both TRα1 and TRβ1 without any significant selectivity.

Design of thyromimetic small molecule agents led to the identificationof TR (or THR) agonists with varying levels of TRβ selectivity despitehigh structural similarity between the ligand-binding domains for TRβand TRα. TRβ selectivity achieved by some of these compounds resulted inan improved therapeutic index for lipid lowering relative to cardiaceffects such as heart rate, cardiac hypertrophy, and contractility[10-12].

Another strategy to avoid activation of TRα in cardiac tissue is todesign prodrugs of phosphonate-containing TR agonists that arespecifically converted to the active agonist in the liver but remainstable as an inactive prodrug in blood and extrahepatic tissues,including the heart [13]. TRα and TRβ agonists are also used inindications other than liver-related disorders, as has been known in theart.

SUMMARY

Disclosed herein are compounds of Formula I′:

TL-L_(a)-CE-HD  (I′)

or a pharmaceutically acceptable salt, prodrug, amide or ester thereof,where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId;ii) L_(a) is independently a bond; —(C(R_(a))₂)_(n)—; oxygen; sulfur;—NR_(a)— iii) CE is a moiety of Formula IV; iv) HD is a moiety ofFormula V or VI; where the substituents are as defined herein. Disclosedare also pharmaceutical compositions comprising the above compounds, andmethods of treating disease by administering or contact a patient withone or more of the above compounds.

BRIEF DESCRIPTION OF THF DRAWINGS

FIG. 1 depicts the chemical structure of Compound 67 as confirmed byx-ray crystallography.

FIG. 2 depicts the chemical structure of Compound 67-A as confirmed byx-ray crystallography.

DETAILED DESCRIPTION OF THF EMBODIMENTS

Disclosed herein are novel compounds that are effective modulators ofTHR-0 activity that can be used for the treatment of various THR-0related disorders. The compounds and the methods of their use arediscussed in detail below. Certain of the compounds disclosed herein areagonists, while others are antagonists, of TRα and/or TRβ receptors andare used to treat liver-related disorders and other indications known inthe art that are mediated by TRα and/or TRβ receptors.

Definitions

Various embodiments are described hereinafter. It should be noted thatthe specific embodiments are not intended as an exhaustive descriptionor as a limitation to the broader aspects discussed herein. One aspectdescribed in conjunction with a particular embodiment is not necessarilylimited to that embodiment and can be practiced with any otherembodiment(s).

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the elements (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein are merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range, unless otherwise indicated herein, andeach separate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the embodiments and does not pose alimitation on the scope of the claims unless otherwise stated. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential.

In the definition of chemical substituents, each of Rx and Ry isindependently hydrogen, alkyl, carbocyclic ring, heterocyclic ring,aryl, or heteroaryl, all of which, except hydrogen, are optionallysubstituted.

Unless otherwise indicated, the abbreviations “TR” and “THR” refer tothyroid hormone receptors.

As used herein, “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to a patient towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreaction of a compound disclosed herein with an acid or base.Base-formed salts include, without limitation, ammonium salt (NH₄ ⁺);alkali metal, such as, without limitation, sodium or potassium, salts;alkaline earth, such as, without limitation, calcium or magnesium,salts; salts of organic bases such as, without limitation,dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine;and salts with the amino group of amino acids such as, withoutlimitation, arginine and lysine. Useful acid-based salts include,without limitation, hydrochlorides, hydrobromides, sulfates, nitrates,phosphates, methane-sulfonates, ethanesulfonates, p-toluenesulfonatesand salicylates.

As used herein, “pharmaceutically acceptable ester” refers to an esterof a compound that does not cause significant irritation to a patient towhich it is administered. The ester is metabolized in the body to resultin the parent compound, e.g., the claimed compound. Accordingly, theester does not abrogate the biological activity and properties of thecompound. Pharmaceutical esters can be obtained by reaction of acompound disclosed herein with an alcohol. Methyl, ethyl, and isopropylesters are some of the common esters to be prepared. Other esterssuitable are well-known to those skilled in the art (see, for exampleWuts, P.G.M., Greene's Protective Groups in Organic Synthesis, 5^(th)Ed., John Wiley & Sons, New York, N.Y., 2014, which is incorporatedherein by reference in its entirety).

Where the compounds disclosed herein have at least one chiral center,they may exist as a racemate or as individual enantiomers. It should benoted that all such isomers and mixtures thereof are included in thescope of the present disclosure. Thus, the illustration of a chiralcenter without a designation of R or S signifies that the scope of thedisclosure includes the R isomer, the S isomer, the racemic mixture ofthe isomers, or mixtures where one isomer is present in greaterabundance than the other.

Where the processes for the preparation of the compounds disclosedherein give rise to mixtures of stereoisomers, such isomers may beseparated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form orindividual enantiomers may be prepared by stereoselective synthesis orby resolution. The compounds may be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides followed by chromatographicseparation and removal of the chiral auxiliary.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted” it is meant that the substituent is a groupthat may be substituted with one or more group(s) individually andindependently selected, without limitation, from alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy,aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl,thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl,N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, is O-cyanato, thiocyanato, isothiocyanato, nitro,silyl, trihalomethanesulfonyl, and amino, including mono- anddi-substituted amino groups, and the protected derivatives thereof. Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Wuts, above.

As used herein, a “carbocyclic ring” is a ring structure in which allthe atoms in the ring are carbon atoms. If any of the atoms in the ringis anything other than a carbon atom, then the ring is a “heterocyclicring.” Examples of atoms that are within a ring include sulfur, oxygen,and nitrogen. A carbocyclic ring or a heterocyclic ring may bepolycyclic, e.g., a fused ring system, a spirocyclic ring system, or abridged ring system. These polycyclic rings include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Additionalnon-limiting examples include:

As used herein, “aryl” refers to a carbocyclic (all carbon) ring thathas a fully delocalized pi-electron system. The “aryl” group can be madeup of two or more fused rings (rings that share two adjacent carbonatoms). When the aryl is a fused ring system, then the ring that isconnected to the rest of the molecule has a fully delocalizedpi-electron system. The other ring(s) in the fused ring system may ormay not have a fully delocalized pi-electron system. Examples of arylgroups include, without limitation, the radicals of benzene, naphthaleneand azulene. Additional non-limiting examples include:

As used herein, “heteroaryl” refers to a ring that has a fullydelocalized pi-electron system and contains one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur inthe ring. The “heteroaryl” group can be made up of two or more fusedrings (rings that share two adjacent carbon atoms). When the heteroarylis a fused ring system, then the ring that is connected to the rest ofthe molecule has a fully delocalized pi-electron system. The otherring(s) in the fused ring system may or may not have a fully delocalizedpi-electron system. Examples of heteroaryl rings include, withoutlimitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole,imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole,pyridine, pyridazine, pyrimidine, pyrazine and triazine.

Wherever “hetero” is used it is intended to mean a group as specified,such as an alkyl or an aryl group, where at least one carbon atom hasbeen replaced with a heteroatom selected from nitrogen, oxygen andsulfur.

As used herein, “alkyl” refers to a straight or branched chain fullysaturated (no double or triple bonds) hydrocarbon group. An alkyl groupof the presently disclosed compounds may comprise from 1 to 20 carbonatoms. An alkyl group herein may also be of medium size having 1 to 10carbon atoms. An alkyl group herein may also be a lower alkyl having 1to 5 carbon atoms. Examples of alkyl groups include, without limitation,methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl,t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl anddodecyl.

An alkyl group of the presently disclosed compounds may be substitutedor unsubstituted. When substituted, the substituent group(s) can be oneor more group(s) independently selected from cycloalkyl, aryl,heteroaryl, heteroalicyclyl, hydroxy, protected hydroxy, alkoxy,aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl,thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl,N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, silyl, trihalomethanesulfonyl, —NR_(x)R_(y) andprotected amino.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Analkenyl group of the presently disclosed compounds may be unsubstitutedor substituted. When substituted, the substituent(s) may be selectedfrom the same groups disclosed above regarding alkyl group substitution,or with regard to optional substitution.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Analkynyl group of the presently disclosed compounds may be unsubstitutedor substituted. When substituted, the substituent(s) may be selectedfrom the same groups disclosed above regarding alkyl group substitution,or with regard to optional substitution.

As used herein, “acyl” refers to an “R_(x)C(═O)—” group.

As used herein, “cycloalkyl” refers to a completely saturated (no doublebonds) hydrocarbon ring. Cycloalkyl groups of the presently disclosedcompounds may range from C₃ to C₈. A cycloalkyl group may beunsubstituted or substituted. If substituted, the substituent(s) may beselected from those indicated above regarding substitution of an alkylgroup. The “cycloalkyl” group can be made up of two or more fused rings(rings that share two adjacent carbon atoms). When the cycloalkyl is afused ring system, then the ring that is connected to the rest of themolecule is a cycloalkyl as defined above. The other ring(s) in thefused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, aheteroaryl, or a heteroalicyclic.

As used herein, “cycloalkenyl” refers to a cycloalkyl group thatcontains one or more double bonds in the ring although, if there is morethan one, they cannot form a fully delocalized pi-electron system in thering (otherwise the group would be “aryl,” as defined herein). Acycloalkenyl group of the presently disclosed compounds mayunsubstituted or substituted. When substituted, the substituent(s) maybe selected from the same groups disclosed above regarding alkyl groupsubstitution. The “cycloalkenyl” group can be made up of two or morefused rings (rings that share two adjacent carbon atoms). When thecycloalkenyl is a fused ring system, then the ring that is connected tothe rest of the molecule is a cycloalkenyl as defined above. The otherring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, anaryl, a heteroaryl, or a heteroalicyclic.

The term “alkylene” refers to an alkyl group, as defined herein, whichis a biradical and is connected to two other moieties. Thus, methylene(—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), isopropylene(IUPAC: (methyl)ethylene) (—CH₂—CH(CH₃)—), and isobutylene (IUPAC:2-(methyl)propylene) (—CH₂—CH(CH₃)—CH₂—) are examples, withoutlimitation, of an alkylene group. Similarly, the term “cycloalkylene”refers to a cycloalkyl group, as defined here, which binds in ananalogous way to two other moieties. If the alkyl and cycloalkyl groupscontain unsaturated carbons, the terms “alkenylene” and“cycloalkenylene” are used.

As used herein, “heterocycloalkyl,” “heteroalicyclic,” or“heteroali-cyclyl” refers to a ring having in the ring system one ormore heteroatoms independently selected from nitrogen, oxygen andsulfur. The ring may also contain one or more double bonds provided thatthey do not form a fully delocalized pi-electron system in the rings.The ring defined herein can be a stable 3- to 18-membered ring thatconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur. Heteroalicyclylgroups of the presently disclosed compounds may be unsubstituted orsubstituted. When substituted, the substituent(s) may be one or moregroups independently selected from the group consisting of halogen,hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy,carboxy, protected carboxy, amino, protected amino, carboxamide,protected carboxamide, alkylsulfonamido andtrifluoromethane-sulfonamido. The “heterocycloalkyl” group can be madeup of two or more fused rings (rings that share two adjacent carbonatoms). When the heterocycloalkyl is a fused ring system, then the ringthat is connected to the rest of the molecule is a heterocycloalkyl asdefined above. The other ring(s) in the fused ring system may be acycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.

As used herein, “aralkyl” refers to an alkylene substituted with an arylgroup.

As used herein, “carbocyclic alkyl” or “(carbocyclic)alkyl” refers to analkylene substituted with a carbocyclic group.

As used herein, “heterocyclicalkyl” or (heterocyclic)alkyl” refers to analkylene substituted with a heterocyclic group. Similarly,“(heterocycloalkyl)alkyl” refers to an alkylene substituted with aheterocycloalkyl group.

As used herein, “heteroarylalkyl” or “(heteroaryl)alkyl” refers to analkylene substituted with a heteroaryl group.

An “O-carboxy” group refers to a “R_(x)C(═O)O—” group.

A “C-carboxy” group refers to a “—C(═O)R” group.

An “acetyl” group refers to a CH₃C(═O)— group.

A “C-amido” group refers to a “—C(═O)NR_(x)R_(y)” group.

An “N-amido” group refers to a “RC(═O)NR_(x)—” group.

The term “perhaloalkyl” refers to an alkyl group in which all thehydrogen atoms are replaced by halogen atoms.

Any unsubstituted or monosubstituted amine group on a compound hereincan be converted to an amide, any hydroxy group can be converted to anester and any carboxyl group can be converted to either an amide orester using techniques well-known to those skilled in the art (see, forexample Wuts, above).

It is understood that, in any compound of the presently disclosedcompounds having one or more chiral centers, if an absolutestereochemistry is not expressly indicated, then each center mayindependently be R or S or a mixture thereof. In addition, it isunderstood that, in any compound of the presently disclosed compoundshaving one or more double bond(s) generating geometrical isomers thatcan be defined as E or Z each double bond may independently be E or Z,or a mixture thereof.

It is understood that the disclosure of a compound herein inherentlyincludes the disclosure of a tautomer thereof, if applicable. Forinstance, the disclosure of:

also includes the disclosure of:

and vice versa, even if only one of the two structures is disclosed.

Throughout the present disclosure, when a compound is illustrated ornamed, it is understood that the isotopically enriched analogs of thecompound are also contemplated. For example, a compound may have adeuterium incorporated instead of a hydrogen, or a carbon-13 instead ofcarbon with natural isotopic distribution. The isotopic enrichment maybe in one location on the compound, i.e., only one hydrogen is replacedby a deuterium, or in more than one location. The present disclosurealso encompasses compounds where all the similar atoms are replaced bytheir less common isotope, for example, a perdeutero compound where allthe hydrogen atoms are replaced by a deuterium. The isotopicallyenriched compounds are useful when obtaining NMR spectra or when makinguse of an isotope effect in managing the kinetics of the reaction thecompound undergoing.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to,oral, injection, aerosol, parenteral, and topical administration.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines chemical compounds diluted in water that willdissolve the compound of interest as well as stabilize the biologicallyactive form of the compound. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a compound.

In certain embodiments, the same substance can act as a carrier,diluent, or excipient, or have any of the two roles, or have all threeroles. Thus, a single additive to the pharmaceutical composition canhave multiple functions.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of thecompound.

Compounds

In one aspect, disclosed herein are compounds of Formula I:

TL-L_(a)-CE-HD  (I)

or a pharmaceutically acceptable salt, prodrug, amide or ester thereof,where:

-   -   i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IId:

-   -   where:    -   each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆ and Q₈, is independently nitrogen        or —CR_(b)—, wherein each R_(b) is independently hydrogen,        halogen, or lower alkyl;    -   R₁ is hydrogen, an optionally substituted alkyl, an optionally        substituted carbocyclic group, an optionally substituted aryl        group, an optionally substituted heterocyclic group, an        optionally substituted heteroaryl group, an optionally        substituted carbocyclic alkyl group, an optionally substituted        aralkyl group, an optionally substituted heterocyclicalkyl        group, an optionally substituted heteroarylalkyl group, an        optionally substituted amino group, an optionally substituted        C-carboxy or O-carboxy group, —CN, an optionally substituted        carbamoyl group, or an optionally substituted carbamoyl alkyl        group, where the nitrogen of the carbamoyl or carbamoyl alkyl        group is optionally a heteroatom in a ring structure;    -   R₂ is hydrogen, halogen, optionally substituted alkyl,        optionally substituted cycloalkyl, or —CN;    -   R₃ is hydrogen or lower alkyl;    -   R₄ is an optionally substituted alkyl, an optionally substituted        carbocyclic group, an optionally substituted aryl group, an        optionally substituted heterocyclic group, an optionally        substituted heteroaryl group, an optionally substituted        carbocyclic alkyl group, an optionally substituted aralkyl        group, an optionally substituted heterocyclicalkyl group, an        optionally substituted heteroarylalkyl group, an optionally        substituted amino group, an optionally substituted sulfamoyl        group, an optionally substituted carbamoyl group, or an        optionally substituted carbamoyl alkyl group, where the nitrogen        of the carbamoyl or carbamoyl alkyl group is optionally a        heteroatom in a ring structure; and    -   R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or        alkylsulfonylamino;    -   or R₄ and R₅ taken together along with the carbon atoms to which        they are attached form a five- or six-membered optionally        substituted carbocyclic group, optionally substituted aryl        group, optionally substituted heterocyclic group, or optionally        substituted heteroaryl group;    -   or R₄ and R₅ taken together along with the carbon atoms to which        they are attached form a seven to eleven membered, optionally        substituted spirocyclic ring or a seven to eleven membered,        optionally substituted spiro-heterocyclic ring; and    -   Alk is hydrogen or an optionally substituted alkyl;    -   ii) CE is a moiety of Formula IV

wherein:

-   -   each of R₆ and R₇ is independently selected from halogen, —CN,        optionally substituted lower alkyl, optionally substituted lower        alkoxy, optionally substituted lower alkenyl, or cyclopropyl;    -   R₈ is selected from hydrogen, optionally substituted lower        alkyl, optionally substituted lower alkoxy, cyano, or halogen;    -   optionally R₇ and R₈ taken together, along with the carbon atoms        to which they are attached, form a 4, 5- or 6-membered        carbocyclic, heterocyclic, aryl, or heteroaryl ring    -   Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen,        or lower alkyl;    -   (TL) denotes the point where the moiety of Formula IV connects        to TL-L_(a)-; and    -   (HD) denotes the point where the moiety of Formula IV connects        to -HD;    -   iii) HD is a moiety of Formula V or VI:

wherein:

-   -   R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(d))₃,        —(C(R_(d))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(a))₂,        —(C(R_(d))₂)_(n)—S(═O)_(q)R_(d), —(C(R_(d))₂)_(n)—CN,        —(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),        —(C(R_(d))₂)_(n)—HeAr, or —(C(R_(d))₂)_(n)—C(═O)—N(R_(a))₂;        wherein        -   each R_(d) is independently hydrogen or optionally            substituted lower alkyl;        -   each q is independently selected from 0, 1, or 2;        -   each n is independently selected from 0, 1, 2, 3, 4, or 5;            and        -   HeAr is a 5- or 6-membered heteroaryl.    -   R₁₀ is hydrogen, —C(R_(e))₃, wherein each R_(e) is independently        hydrogen, halogen, or optionally substituted lower alkyl; and    -   R₁₁ is an aryl group, optionally substituted with lower alkyl,        halogen, cycloalkyl; or a bicyclic ring system containing either        aromatic or saturated rings; or a bicyclic heterocyclic        containing either aromatic or saturated ring systems    -   iv) L_(a) is independently a bond; —(C(R_(a))₂)_(n)—; oxygen;        sulfur; —NR_(a)—; wherein:    -   each R_(a) is independently a hydrogen or lower alkyl; and    -   n is 0, 1, 2, 3, 4 or 5.

In some embodiments, R₁ is an optionally substituted alkyl, anoptionally substituted carbocyclic group, an optionally substituted arylgroup, and an optionally substituted C-carboxy or O-carboxy group. Insome of these embodiments, the alkyl is selected from the groupconsisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, andt-butyl. In certain embodiments, the carbocyclic group is cyclohexane orcyclopentane. In various embodiments, the aryl group is phenyl. In someembodiments, the C-carboxy group is a moiety of formula —C(═O)—O—R andthe O-carboxy group a moiety of formula —O—C(═O)—R, where R is selectedfrom the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl.

In some embodiments, R₂ is selected from the group consisting ofhydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, andt-butyl.

In some embodiments, Q₁, Q₂, Q₃, and Q₄ are —CR_(b)—, where each R_(b)is independently selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

In some embodiments, R₄ is selected from the group consisting of methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

In some embodiments, R₅ is hydroxy.

In some embodiments, TL is a moiety selected from:

In some embodiments, TL is a moiety selected from:

In some embodiments of the compound of Formula I, each of R₆ and R₇ isindependently chlorine, bromine, and iodine. In other embodiments, eachof R₆ and R₇ is independently —CN, an optionally substituted lower alkylor an optionally substituted lower alkoxy, where the lower alkyl and thealkyl group of the lower alkoxy is each independently selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. Insome embodiments, R₆ and R₇ are the same. In certain embodiments, eachof R₆ and R₇ is independently chlorine or methyl.

In some embodiments of the compound of Formula I, R₈ is hydrogen.

In some embodiments, R_(c) is hydrogen or methyl.

In some embodiments, disclosed herein are compounds of Formula I, where:

-   -   TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId;

where:

-   -   each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆ and Q₈, is independently nitrogen        or —CR_(b)—, wherein each R_(b) is independently hydrogen,        halogen, or lower alkyl;    -   R₁ is an optionally substituted alkyl, an optionally substituted        carbocyclic group, an optionally substituted aryl group, an        optionally substituted heterocyclic group, an optionally        substituted heteroaryl group, an optionally substituted        carbocyclic alkyl group, an optionally substituted aralkyl        group, an optionally substituted heterocyclicalkyl group, an        optionally substituted heteroarylalkyl group, an optionally        substituted amino group, an optionally substituted C-carboxy or        O-carboxy group, —CN, an optionally substituted carbamoyl group,        or an optionally substituted carbamoyl alkyl group, where the        nitrogen of the carbamoyl or carbamoyl alkyl group is optionally        a heteroatom in a ring structure;    -   R₂ is halogen, optionally substituted alkyl, optionally        substituted cycloalkyl, or —CN;    -   R₃ is hydrogen    -   R₄ is an optionally substituted alkyl, an optionally substituted        carbocyclic group, an optionally substituted aryl group, an        optionally substituted heterocyclic group, an optionally        substituted heteroaryl group, an optionally substituted        carbocyclic alkyl group, an optionally substituted aralkyl        group, an optionally substituted heterocyclicalkyl group, an        optionally substituted heteroarylalkyl group, an optionally        substituted amino group, an optionally substituted sulfamoyl        group, an optionally substituted carbamoyl group, or an        optionally substituted carbamoyl alkyl group, where the nitrogen        of the carbamoyl or carbamoyl alkyl group is optionally a        heteroatom in a ring structure; and    -   R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or        alkylsulfonylamino;    -   or R₄ and R₅ taken together along with the carbon atoms to which        they are attached form a five- or six-membered optionally        substituted carbocyclic group, optionally substituted aryl        group, optionally substituted heterocyclic group, or optionally        substituted heteroaryl group;    -   or R₄ and R₅ taken together along with the carbon atoms to which        they are attached form a seven to eleven membered, optionally        substituted spirocyclic ring or a seven to eleven membered,        optionally substituted spiro-heterocyclic ring;    -   or when Q₆ is nitrogen and R₅ is hydroxy, then the tautomer of        the moiety of Formula III; and    -   Alk is hydrogen or an optionally substituted alkyl;    -   CE is a moiety of Formula IV

where:

-   -   each of R₆ and R₇ is independently selected from halogen, —CN,        optionally substituted lower alkyl, optionally substituted lower        alkoxy, optionally substituted lower alkenyl, or cyclopropyl;    -   R₈ is selected from hydrogen, optionally substituted lower        alkyl, optionally substituted lower alkoxy, cyano, or halogen;    -   Q₇ is nitrogen or —CR_(c)—, where R_(c) is hydrogen, halogen, or        lower alkyl;    -   (TL) denotes the point where the moiety of Formula IV connects        to TL-L_(a)-; and    -   (HD) denotes the point where the moiety of Formula IV connects        to -HD;    -   HD is a moiety of Formula V or VI:

where

-   -   R₉ is —NH₂ and R₁₀ is —CH₃; and    -   L_(a) is oxygen.

In other embodiments, disclosed herein are compounds of Formula I,where:

-   -   TL is a moiety of Formula II:

where:

-   -   each of Q₁, Q₂, and Q₃ is independently nitrogen or —CR_(b)—,        where each R_(b) is independently hydrogen, halogen, or lower        alkyl;    -   R₁ is an optionally substituted alkyl, an optionally substituted        carbocyclic group, an optionally substituted aryl group, an        optionally substituted heterocyclic group, an optionally        substituted heteroaryl group, an optionally substituted        carbocyclic alkyl group, an optionally substituted aralkyl        group, an optionally substituted heterocyclicalkyl group, an        optionally substituted heteroarylalkyl group, an optionally        substituted amino group, an optionally substituted C-carboxy or        O-carboxy group, —CN, an optionally substituted carbamoyl group,        or an optionally substituted carbamoyl alkyl group, where the        nitrogen of the carbamoyl or carbamoyl alkyl group is optionally        a heteroatom in a ring structure;    -   R₂ is halogen, optionally substituted alkyl, optionally        substituted cycloalkyl, or —CN;    -   R₃ is hydrogen;    -   CE is a moiety of Formula IV

where:

-   -   each of R₆ and R₇ is independently selected from halogen, —CN,        optionally substituted lower alkyl, optionally substituted lower        alkoxy, optionally substituted lower alkenyl, or cyclopropyl;    -   R₈ is selected from hydrogen, optionally substituted lower        alkyl, optionally substituted lower alkoxy, cyano, or halogen;    -   Q₇ is nitrogen or —CR_(c)—, where R_(c) is hydrogen, halogen, or        lower alkyl;    -   (TL) denotes the point where the moiety of Formula IV connects        to TL-L_(a)-; and    -   (HD) denotes the point where the moiety of Formula IV connects        to -HD;    -   HD is a moiety of Formula V:

where

-   -   R₉ is hydrogen, —CN or —C≡C—R_(a), where R_(d) is hydrogen or        lower alkyl; and    -   L_(a) is oxygen.

In some embodiments, La is a combination of two or more of a bond;—(C(R_(a))₂)_(n)—; oxygen; sulfur; or —NR_(a)—.

In another aspect, disclosed herein are compounds of Formula I′:

TL-L_(a)-CE-HD  (I′)

or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt, prodrug, amide or ester thereof, wherein:

-   -   i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or        IIId:

wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, and Q₈, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is hydrogen, an optionally substituted alkyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, an optionally substituted aminogroup, an optionally substituted C-carboxy or O-carboxy group, —CN, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure;

R₂ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or —CN;

R₃ is hydrogen or lower alkyl;

R₄ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted non-aromatic carbocyclic group, anoptionally substituted aryl group, an optionally substitutedheterocyclic group, an optionally substituted heteroaryl group, anoptionally substituted (carbocyclic)alkyl group, an optionallysubstituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted sulfamoyl group, an optionally substitutedcarbamoyl group, or an optionally substituted carbamoyl alkyl group,where the nitrogen of the carbamoyl or carbamoyl alkyl group isoptionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutednon-aromatic carbocyclic group, optionally substituted aryl group,optionally substituted heterocyclic group, or optionally substitutedheteroaryl group;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

Alk is hydrogen or an optionally substituted alkyl; and

R₁₁ is an aryl group optionally substituted with one to fivesubstituents independently selected from lower alkyl, alkoxy,haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionallysubstituted with one to five substituents independently selected fromlower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclicring system; or a bicyclic heterocyclic ring system;

-   -   ii) CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

optionally R₇ and R₈ taken together, along with the carbon atoms towhich they are attached, form a 4-, 5- or 6-membered non-aromaticcarbocyclic, heterocycloalkyl, aryl, or heteroaryl ring

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

-   -   iii) HD is a moiety of Formula V or VI:

wherein:

R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(d))₃,—(C(R_(a))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(d))₂,—(C(R_(d))₂)_(n)—S(═O)_(q)R_(d), —(C(R_(d))₂)_(n)—CN,—(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),—(C(R_(a))₂)_(n)—HeAr, or —(C(R_(d))₂)_(n)—C(═O)—N(R_(d))₂; wherein

each R_(d) is independently hydrogen or optionally substituted loweralkyl;

each q is independently selected from 0, 1, or 2;

each n is independently selected from 0, 1, 2, 3, 4, or 5;

HeAr is a 5- or 6-membered heteroaryl; and

R₁₀ is hydrogen or —C(R_(e))₃, wherein each R_(e) is independentlyhydrogen, halogen, or optionally substituted lower alkyl; and

L_(a) is independently a bond; —(C(R_(a))₂)_(z)—; oxygen; sulfur; or—NR_(a)—; wherein:

each R_(a) is independently a hydrogen or lower alkyl; and

z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of Formula IIIa, wherein Q₄, Q₅, and Q₆ are—CH—, and R₄ is an optionally substituted C₁-C₃alkyl group, anoptionally substituted sulfamoyl group, or an optionally substitutedcarbamoyl group; HD is a moiety of Formula V, wherein R₉ is H or —CN;and Q₇ is —CH—, then R₅ cannot be hydroxy;

(2) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are —CH—,R₁ is —CH₃, and R₂ is hydrogen; HD is a moiety of Formula V, wherein R₉is hydrogen; Q₇ is —CH—; R₆ is halogen or methyl; and R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a5-membered non-aromatic carbocyclic ring, then R₄ and R₅ taken togetheralong with the carbon atoms to which they are attached cannot form afive-membered heteroaryl group;

(3) when TL is a moiety of Formula IIIa, wherein Q₄ is nitrogen, Q₅ andQ₆ are —CH—, and R₅ is —OH; HD is a moiety of Formula V, wherein R₉ is—CN; Q₇ is —CH—; L_(a) is —CH₂—, then R₄ cannot be cyclohexyl,cycloheptyl, isopropyl, or optionally substituted benzene;

(4) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; HD is a moiety of Formula V, wherein R₉ is hydrogen, —CN, or—CO₂H; Q₇ is —CH—; and R₆ and R₇ are independently halogen or methyl, orR₇ and R₈ taken together, along with the carbon atoms to which they areattached, form a 5-membered non-aromatic carbocyclic ring, then R₄cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

(5) when TL is a moiety of Formula IIIb, wherein Q₄ is —CR_(c)— and Q₅is nitrogen; HD is a moiety of Formula V, wherein R₉ is —CN; Q₇ is —CH—;and L_(a) is —O—, then

-   -   (a) none of R₆, R₇, and R₈ can be deuterium;    -   (b) Q₄ cannot be -CD-, wherein D is deuterium; and    -   (c) R₄ cannot be a three- to five-membered cycloalkyl ring        optionally substituted with one or more halogens; non-aromatic        (carbocyclic)alkyl optionally substituted with methyl or        hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl;        phenyl; benzyl optionally substituted with methyl, halogen,        hydroxy, or methoxy; phenethyl optionally substituted with        halogen; C₁-C₄ alkyl optionally substituted with one to six        substituents selected from halogen, hydroxyl, and deuterium;        (tetrahydro-2H-pyran-4-yl)methyl; or a three- to five-membered        heterocycloalkyl optionally substituted with benzyl;

(6) when TL is a moiety of Formula IIIb, wherein (i) Q₄ and Q₅ arenitrogen, (ii) Q₄ and Q₅ are —CR_(b)—, or (iii) Q₄ is nitrogen and Q₅ is—CR_(c)—; HD is a moiety of Formula V, wherein R₉ is —CN; and Q₇ is—CH—; then R₄ cannot be —CH(CH₃)₂ or —CH(CD₃)₂;

(7) when TL is a moiety of Formula IIIa, wherein Q₄ is —CH—, Q₅ and Q₆are nitrogen, and R₄ is isopropyl; HD is a moiety of Formula V, whereinR₉ is —CN; and Q₇ is —CH—; then R₅ cannot be —NH₂ or —NHCH₃;

(8) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; and HD is a moiety of Formula V,then R₉ cannot be methyl;

(9) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH—, Q₅ isnitrogen, and R₄ is isopropyl; L_(a) is —O—; Q₇ is —CH—; and HD is amoiety of Formula V, then R₉ cannot be isopropyl;

(10) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are—CH—; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are independently chlorine ortrifluoromethyl; and HD is a moiety of Formula V, wherein R₉ is —CN ormethyl, then R₁ cannot be isopropyl, 4-tetrahydropyranyl, or —C(O)NH₂;

(11) when TL is a moiety of Formula IIa, wherein Q₁ and Q₂ are —CH—, andQ₃ is nitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HDis a moiety of Formula V, wherein R₉ is —CN, then R₁ cannot beisopropyl;

(12) when TL is a moiety of Formula IIb, wherein Q₁, Q₂, and Q₃ are—CH—; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula V, wherein R₉ is —CN, then R₁ cannot be isopropyl;

(13) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula VI, wherein R₁₀ is H, Me, Et, isopropyl, —CH₂CF₃, or—CH₂CHF₂, then R₄ cannot be C₂-C₅ alkyl or C₁-C₃ hydroxyalkyl;

(14) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula VI, wherein R₁₀ is H or Me, then R₄ cannot becyclopropyl; and

(15) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —CH₂—; Q₇ is —CH—; R₆ and R₇ are both chlorine orboth methyl; and HD is a moiety of Formula VI, wherein R₁₀ is H or Me,then R₄ cannot be isopropyl.

In some embodiments, when TL is a moiety of Formula IIIb, wherein Q₄ is—CH— and Q₅ is nitrogen; HD is a moiety of Formula V, wherein R₉ is—CH₂CN or —C≡CH; Q₇ is —CH—; and R₆ and R₇ are chlorine, then R₄ cannotbe isopropyl.

In another aspect, disclosed herein are compounds of Formula I′:

TL-L_(a)-CE-HD  (I′)

or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt, prodrug, amide or ester thereof, wherein:

-   -   i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IId:

wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, and Q₈, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is hydrogen, an optionally substituted alkyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, an optionally substituted aminogroup, an optionally substituted C-carboxy or O-carboxy group, —CN, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure;

R₂ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or —CN;

R₃ is hydrogen or lower alkyl;

R₄ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted non-aromatic carbocyclic group, anoptionally substituted aryl group, an optionally substitutedheterocyclic group, an optionally substituted heteroaryl group, anoptionally substituted (carbocyclic)alkyl group, an optionallysubstituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted sulfamoyl group, an optionally substitutedcarbamoyl group, or an optionally substituted carbamoyl alkyl group,where the nitrogen of the carbamoyl or carbamoyl alkyl group isoptionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutednon-aromatic carbocyclic group, optionally substituted aryl group,optionally substituted heterocyclic group, or optionally substitutedheteroaryl group;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

Alk is hydrogen or an optionally substituted alkyl; and

R₁₁ is an aryl group optionally substituted with one to fivesubstituents independently selected from lower alkyl, alkoxy,haloalkoxy, halogen, and cycloalkyl; or a heteroaryl group optionallysubstituted with one to five substituents independently selected fromlower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl; or a bicyclicring system; or a bicyclic heterocyclic ring system;

-   -   ii) CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

optionally R₇ and R₈ taken together, along with the carbon atoms towhich they are attached, form a 4-, 5- or 6-membered non-aromaticcarbocyclic, heterocycloalkyl, aryl, or heteroaryl ring

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

-   -   iii) HD is a moiety of Formula V or VI:

wherein:

R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(d))₃,—(C(R_(a))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(d))₂,—(C(R_(d))₂)_(n)—S(═O)_(q)R_(d), —(C(R_(d))₂)_(n)—CN,—(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),—(C(R_(a))₂)_(n)—HeAr, or —(C(R_(a))₂)_(n)—C(═O)—N(R_(d))₂; wherein

each R_(d) is independently hydrogen or optionally substituted loweralkyl;

each q is independently selected from 0, 1, or 2;

each n is independently selected from 0, 1, 2, 3, 4, or 5;

HeAr is a 5- or 6-membered heteroaryl; and

R₁₀ is hydrogen or —C(R_(e))₃, wherein each R_(e) is independentlyhydrogen, halogen, or optionally substituted lower alkyl; and

-   -   (iv) L_(a) is independently a bond; —(C(R_(a))₂)_(z)—; oxygen;        sulfur; or —NR_(a)—; wherein:

each R_(a) is independently a hydrogen or lower alkyl; and

z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of Formula IIIa, wherein Q₄, Q₅, and Q₆ are—CH—, and R₄ is an optionally substituted C₁-C₃alkyl group, anoptionally substituted sulfamoyl group, or an optionally substitutedcarbamoyl group; HD is a moiety of Formula V, wherein R₉ is H or —CN;and Q₇ is —CH—, then R₅ cannot be hydroxy;

(2) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are —CH—,R₁ is —CH₃, and R₂ is hydrogen; HD is a moiety of Formula V, wherein R₉is hydrogen; Q₇ is —CH—; R₆ is halogen or methyl; and R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a5-membered non-aromatic carbocyclic ring, then R₄ and R₅ taken togetheralong with the carbon atoms to which they are attached cannot form afive-membered heteroaryl group;

(3) when TL is a moiety of Formula IIIa, wherein Q₄ is nitrogen, Q₅ andQ₆ are —CH—, and R₅ is —OH; HD is a moiety of Formula V, wherein R₉ is—CN; Q₇ is —CH—; L_(a) is —CH₂—, then R₄ cannot be cyclohexyl,cycloheptyl, isopropyl, or optionally substituted benzene;

(4) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; HD is a moiety of Formula V, wherein R₉ is hydrogen, —CN, or—CO₂H; Q₇ is —CH—; and R₆ and R₇ are independently halogen or methyl, orR₇ and R₈ taken together, along with the carbon atoms to which they areattached, form a 5-membered non-aromatic carbocyclic ring, then R₄cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

(5) when TL is a moiety of Formula IIIb, wherein Q₄ is —CR_(c)— and Q₅is nitrogen; HD is a moiety of Formula V, wherein R₉ is —CN; Q₇ is —CH—;and L_(a) is —O—, then

-   -   (a) none of R₆, R₇, and R₈ can be deuterium;    -   (b) Q₄ cannot be -CD-, wherein D is deuterium; and    -   (c) R₄ cannot be a three- to five-membered cycloalkyl ring        optionally substituted with one or more halogens; non-aromatic        (carbocyclic)alkyl optionally substituted with methyl or        hydroxy; (1H-pyrazol-4-yl)methyl; (3-methylisoxazol-5-yl)methyl;        phenyl; benzyl optionally substituted with methyl, halogen,        hydroxy, or methoxy; phenethyl optionally substituted with        halogen; C₁-C₄ alkyl optionally substituted with one to six        substituents selected from halogen, hydroxyl, and deuterium;        (tetrahydro-2H-pyran-4-yl)methyl; or a three- to five-membered        heterocycloalkyl optionally substituted with benzyl;

(6) when TL is a moiety of Formula IIIb, wherein (i) Q₄ and Q₅ arenitrogen, (ii) Q₄ and Q₅ are —CR_(b)—, or (iii) Q₄ is nitrogen and Q₅ is—CR_(c)—; HD is a moiety of Formula V, wherein R₉ is —CN; and Q₇ is—CH—; then R₄ cannot be —CH(CH₃)₂ or —CH(CD₃)₂;

(7) when TL is a moiety of Formula IIIa, wherein Q₄ is —CH—, Q₅ and Q₆are nitrogen, and R₄ is isopropyl; HD is a moiety of Formula V, whereinR₉ is —CN; and Q₇ is —CH—; then R₅ cannot be —NH₂ or —NHCH₃;

(8) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; and HD is a moiety of Formula V,then R₉ cannot be methyl;

(9) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH—, Q₅ isnitrogen, and R₄ is isopropyl; L_(a) is —O—; Q₇ is —CH—; and HD is amoiety of Formula V, then R₉ cannot be isopropyl;

(10) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are—CH—; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are independently chlorine ortrifluoromethyl; and HD is a moiety of Formula V, wherein R₉ is —CN ormethyl, then R₁ cannot be isopropyl, 4-tetrahydropyranyl, or —C(O)NH₂;

(11) when TL is a moiety of Formula IIa, wherein Q₁ and Q₂ are —CH—, andQ₃ is nitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HDis a moiety of Formula V, wherein R₉ is —CN, then R₁ cannot beisopropyl;

(12) when TL is a moiety of Formula IIb, wherein Q₁, Q₂, and Q₃ are—CH—; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula V, wherein R₉ is —CN, then R₁ cannot be isopropyl;

(13) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula VI, wherein R₁₀ is H, Me, Et, isopropyl, —CH₂CF₃, or—CH₂CHF₂, then R₄ cannot be C₂-C₅ alkyl or C₁-C₃ hydroxyalkyl;

(14) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —O—; Q₇ is —CH—; R₆ and R₇ are chlorine; and HD is amoiety of Formula VI, wherein R₁₀ is H or Me, then R₄ cannot becyclopropyl;

(15) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; L_(a) is —CH₂—; Q₇ is —CH—; R₆ and R₇ are both chlorine orboth methyl; and HD is a moiety of Formula VI, wherein R₁₀ is H or Me,then R₄ cannot be isopropyl; and

(16) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; HD is a moiety of Formula V, wherein R₉ is —CH₂CN or —C≡CH; Q₇is —CH—; and R₆ and R₇ are chlorine, then R₄ cannot be isopropyl.

In another aspect, disclosed herein are compounds of Formula I′:

TL-L_(a)-CE-HD  (I′)

or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt, prodrug, amide or ester thereof, wherein:

-   -   i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IId:

wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, and Q₈, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is hydrogen, an optionally substituted alkyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, an optionally substituted aminogroup, an optionally substituted C-carboxy or O-carboxy group, —CN, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure;

R₂ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or —CN;

R₃ is hydrogen or lower alkyl;

R₄ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted non-aromatic carbocyclic group, anoptionally substituted aryl group, an optionally substitutedheterocyclic group, an optionally substituted heteroaryl group, anoptionally substituted (carbocyclic)alkyl group, an optionallysubstituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted sulfamoyl group, an optionally substitutedcarbamoyl group, or an optionally substituted carbamoyl alkyl group,where the nitrogen of the carbamoyl or carbamoyl alkyl group isoptionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutednon-aromatic carbocyclic group, optionally substituted aryl group,optionally substituted heterocyclic group, or optionally substitutedheteroaryl group;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

Alk is hydrogen or an optionally substituted alkyl; and

R₁₁ is an aryl group optionally substituted with one to fivesubstituents independently selected from lower alkyl, halogen, andcycloalkyl; or a bicyclic ring system containing either aromatic orsaturated rings; or a bicyclic heterocyclic containing either aromaticor saturated ring systems;

-   -   ii) CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

optionally R₇ and R₈ taken together, along with the carbon atoms towhich they are attached, form a 4-, 5- or 6-membered non-aromaticcarbocyclic, heterocycloalkyl, aryl, or heteroaryl ring

Q₇ is nitrogen or —CR_(c)—, wherein R_(e) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

-   -   iii) HD is a moiety of Formula V or VI:

wherein:

R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(a))₃,—(C(R_(a))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(a))₂,—(C(R_(d))₂)_(n)—S(═O)_(q)R_(a), —(C(R_(d))₂)_(n)—CN,—(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),—(C(R_(a))₂)_(n)—HeAr, or —(C(R_(a))₂)_(n)—C(═O)—N(R_(a))₂; wherein

each R_(d) is independently hydrogen or optionally substituted loweralkyl;

each q is independently selected from 0, 1, or 2;

each n is independently selected from 0, 1, 2, 3, 4, or 5;

HeAr is a 5- or 6-membered heteroaryl; and

R₁₀ is hydrogen or —C(R_(e))₃, wherein each R_(e) is independentlyhydrogen, halogen, or optionally substituted lower alkyl; and

L_(a) is independently a bond; —(C(R_(a))₂)_(z)—; oxygen; sulfur; or—NR_(a)—; wherein:

each R_(a) is independently a hydrogen or lower alkyl; and

z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of Formula IIIa, wherein Q₄, Q₅, and Q₆ are—CH—, and R₄ is an optionally substituted C₁-C₃alkyl group, anoptionally substituted sulfamoyl group, or an optionally substitutedcarbamoyl group; HD is a moiety of Formula V, wherein R₉ is H or —CN;and Q₇ is —CH—, then R₅ cannot be hydroxy;

(2) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are —CH—,R₁ is —CH₃, and R₂ is hydrogen; HD is a moiety of Formula V, wherein R₉is hydrogen; Q₇ is —CH—; R₆ is halogen or methyl; and R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a5-membered non-aromatic carbocyclic ring, then R₄ and R₅ taken togetheralong with the carbon atoms to which they are attached cannot form afive-membered heteroaryl group;

(3) when TL is a moiety of Formula IIIa, wherein Q₄ is nitrogen, Q₅ andQ₆ are —CH—, and R₅ is —OH; HD is a moiety of Formula V, wherein R₉ is—CN; Q₇ is —CH—; L_(a) is —CH₂—, then R₄ cannot be cyclohexyl,cycloheptyl, isopropyl, or optionally substituted benzene;

(4) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; HD is a moiety of Formula V, wherein R₉ is hydrogen, —CN, or—CO₂H; Q₇ is —CH—; and R₆ and R₇ are independently halogen or methyl, orR₇ and R₈ taken together, along with the carbon atoms to which they areattached, form a 5-membered non-aromatic carbocyclic ring, then R₄cannot be isopropyl or 2-hydroxy-1-methyl-ethyl;

(5) when TL is a moiety of Formula IIIb, wherein Q₄ is —CR_(c)— and Q₅is nitrogen; HD is a moiety of Formula V, wherein R₉ is —CN; Q₇ is —CH—;and L_(a) is —O—, then

-   -   (a) none of R₆, R₇, and R₈ can be deuterium;    -   (b) Q₄ cannot be -CD-, wherein D is deuterium; and    -   (c) R₄ cannot be a three- to five-membered cycloalkyl ring        optionally substituted with one or more halogens; C₁-C₄ alkyl        optionally substituted with one to six substituents selected        from halogen, hydroxyl, and deuterium; or a three- to        five-membered heterocycloalkyl;

(6) when TL is a moiety of Formula IIIb, wherein (i) Q₄ and Q₅ arenitrogen, (ii) Q₄ and Q₅ are —CR_(b)—, or (iii) Q₄ is nitrogen and Q₅ is—CR_(c)—; HD is a moiety of Formula V, wherein R₉ is —CN; and Q₇ is—CH—; then R₄ cannot be —CH(CH₃)₂ or —CH(CD₃)₂; and

(7) when TL is a moiety of Formula IIIa, wherein Q₄ is —CH—, Q₅ and Q₆are nitrogen, and R₄ is isopropyl; HD is a moiety of Formula V, whereinR₉ is —CN; and Q₇ is —CH—; then R₅ cannot be —NH₂ or —NHCH₃.

In some embodiments, when TL is a moiety of Formula IIIb, wherein Q₄ is—CH— and Q₅ is nitrogen; HD is a moiety of Formula V, wherein R₉ is—CH₂CN or —C≡CH; Q₇ is —CH—; and R₆ and R₇ are chlorine, then R₄ cannotbe isopropyl.

In another aspect, disclosed herein are compounds of Formula I′:

TL-L_(a)-CE-HD  (I′)

or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt, prodrug, amide or ester thereof, wherein:

-   -   i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or        IIId:

wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, and Q₈, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is hydrogen, an optionally substituted alkyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, an optionally substituted aminogroup, an optionally substituted C-carboxy or O-carboxy group, —CN, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure;

R₂ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or —CN;

R₃ is hydrogen or lower alkyl;

R₄ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted non-aromatic carbocyclic group, anoptionally substituted aryl group, an optionally substitutedheterocyclic group, an optionally substituted heteroaryl group, anoptionally substituted (carbocyclic)alkyl group, an optionallysubstituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted sulfamoyl group, an optionally substitutedcarbamoyl group, or an optionally substituted carbamoyl alkyl group,where the nitrogen of the carbamoyl or carbamoyl alkyl group isoptionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutednon-aromatic carbocyclic group, optionally substituted aryl group,optionally substituted heterocyclic group, or optionally substitutedheteroaryl group;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

Alk is hydrogen or an optionally substituted alkyl; and

R₁₁ is an aryl group optionally substituted with one to fivesubstituents independently selected from lower alkyl, halogen, andcycloalkyl; or a bicyclic ring system containing either aromatic orsaturated rings; or a bicyclic heterocyclic containing either aromaticor saturated ring systems;

-   -   ii) CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

optionally R₇ and R₈ taken together, along with the carbon atoms towhich they are attached, form a 4-, 5- or 6-membered non-aromaticcarbocyclic, heterocycloalkyl, aryl, or heteroaryl ring

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

-   -   iii) HD is a moiety of Formula V or VI:

wherein:

R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(a))₃,—(C(R_(a))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(a))₂,—(C(R_(d))₂)_(n)—S(═O)_(q)R_(a), —(C(R_(d))₂)_(n)—CN,—(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),—(C(R_(a))₂)_(n)—HeAr, or —(C(R_(a))₂)_(n)—C(═O)—N(R_(a))₂; wherein

each R_(d) is independently hydrogen or optionally substituted loweralkyl;

each q is independently selected from 0, 1, or 2;

each n is independently selected from 0, 1, 2, 3, 4, or 5;

HeAr is a 5- or 6-membered heteroaryl; and

R₁₀ is hydrogen or —C(R_(e))₃, wherein each R_(e) is independentlyhydrogen, halogen, or optionally substituted lower alkyl; and

-   -   (iv) L_(a) is independently a bond; —(C(R_(a))₂)_(z)—; oxygen;        sulfur; or —NR_(a)—; wherein:

each R_(a) is independently a hydrogen or lower alkyl; and

z is 0, 1, 2, 3, 4 or 5;

provided that:

(1) when TL is a moiety of Formula IIIa, wherein Q₄, Qs, and Q₆ are—CH—, and R₄ is an optionally substituted C₁-C₃alkyl group, anoptionally substituted sulfamoyl group, or an optionally substitutedcarbamoyl group; HD is a moiety of Formula V, wherein R₉ is H or —CN;and Q₇ is —CH—, then R₅ cannot be hydroxy;

(2) when TL is a moiety of Formula IIa, wherein Q₁, Q₂, and Q₃ are —CH—,R₁ is —CH₃, and R₂ is hydrogen; HD is a moiety of Formula V, wherein R₉is hydrogen; Q₇ is —CH—; R₆ is halogen or methyl; and R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a5-membered non-aromatic carbocyclic ring, then R₄ and R₅ taken togetheralong with the carbon atoms to which they are attached cannot form afive-membered heteroaryl group;

(3) when TL is a moiety of Formula IIIa, wherein Q₄ is nitrogen, Q₅ andQ₆ are —CH—, and R₅ is —OH; HD is a moiety of Formula V, wherein R₉ is—CN; Q₇ is —CH—; L_(a) is —CH₂—, then R₄ cannot be cyclohexyl,cycloheptyl, isopropyl, or optionally substituted benzene;

(4) when TL is a moiety of Formula IIIb, wherein Q₄ is —CH— and Q₅ isnitrogen; HD is a moiety of Formula V, wherein R₉ is hydrogen, —CN,—CH₂CN, —C≡CH, or —CO₂H; Q₇ is —CH—; and R₆ and R₇ are independentlyhalogen or methyl, or R₇ and R₈ taken together, along with the carbonatoms to which they are attached, form a 5-membered non-aromaticcarbocyclic ring, then R₄ cannot be isopropyl or2-hydroxy-1-methyl-ethyl;

(5) when TL is a moiety of Formula IIIb, wherein Q₄ is —CR_(c)— and Q₅is nitrogen; HD is a moiety of Formula V, wherein R₉ is —CN; Q₇ is —CH—;and L_(a) is —O—, then

-   -   (a) none of R₆, R₇, and R₈ can be deuterium;    -   (b) Q₄ cannot be -CD-, wherein D is deuterium; and    -   (c) R₄ cannot be a three- to five-membered cycloalkyl ring        optionally substituted with one or more halogens; C₁-C₄ alkyl        optionally substituted with one to six substituents selected        from halogen, hydroxyl, and deuterium; or a three- to        five-membered heterocycloalkyl;

(6) when TL is a moiety of Formula IIIb, wherein (i) Q₄ and Q₅ arenitrogen, (ii) Q₄ and Q₅ are —CR_(b)—, or (iii) Q₄ is nitrogen and Q₅ is—CR_(c)—; HD is a moiety of Formula V, wherein R₉ is —CN; and Q₇ is—CH—; then R₄ cannot be —CH(CH₃)₂ or —CH(CD₃)₂; and

(7) when TL is a moiety of Formula IIIa, wherein Q₄ is —CH—, Q₅ and Q₆are nitrogen, and R₄ is isopropyl; HD is a moiety of Formula V, whereinR₉ is —CN; and Q₇ is —CH—; then R₅ cannot be —NH₂ or —NHCH₃.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIa, IIb, IIIa, IIIb, IIIc, or IIId;

-   -   wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆ and Q₈, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is an optionally substituted alkyl, an optionally substitutednon-aromatic carbocyclic group, an optionally substituted aryl group, anoptionally substituted heterocycloalkyl group, an optionally substitutedheteroaryl group, an optionally substituted (carbocyclic)alkyl group, anoptionally substituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted C-carboxy or O-carboxy group, —CN, an optionallysubstituted carbamoyl group, or an optionally substituted carbamoylalkyl group, where the nitrogen of the carbamoyl or carbamoyl alkylgroup is optionally a heteroatom in a ring structure;

R₂ is halogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or —CN;

R₃ is hydrogen;

R₄ is an optionally substituted alkyl, an optionally substitutednon-aromatic carbocyclic group, an optionally substituted aryl group, anoptionally substituted heterocycloalkyl group, an optionally substitutedheteroaryl group, an optionally substituted (carbocyclic)alkyl group, anoptionally substituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted sulfamoyl group, an optionally substitutedcarbamoyl group, or an optionally substituted carbamoyl alkyl group,where the nitrogen of the carbamoyl or carbamoyl alkyl group isoptionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutednon-aromatic carbocyclic group, optionally substituted aryl group,optionally substituted heterocycloalkyl group, or optionally substitutedheteroaryl group;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring; and

Alk is hydrogen or an optionally substituted alkyl;

CE is a moiety of Formula IV

-   -   wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

HD is a moiety of Formula V or VI:

-   -   wherein:

R₉ is selected from —NH₂, —CN, —CH₂—S—CH₃, or —CH₂—S(═O)₂—CH₃;

R₁₀ is —CH₃; and

L_(a) is oxygen or —CH₂—.

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIa:

and

HD is a moiety of Formula V:

In some embodiments of the compound of Formula I′:

TL is a moiety of Formula IIa:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′:

TL is a moiety of Formula IIb:

and

HD is a moiety of Formula V:

In some embodiments of the compound of Formula I′:

TL is a moiety of Formula IIb:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIa:

and

HD is a moiety of Formula V:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIa:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIb:

and

HD is a moiety of Formula V:

wherein:

R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—OR_(d),—(C(R_(d))₂)_(n)—N(R_(d))₂, —(C(R_(d))₂)_(n)—S(═O)_(q)R_(d),—(C(R_(d))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),—(C(R_(d))₂)_(n)—HeAr, or —(C(R_(d))₂)_(n)—C(═O)—N(R_(d))₂;

wherein

each R_(d) is independently hydrogen or optionally substituted C₁-C₅alkyl;

each q is independently 0 or 2; and

each n is independently 0 or 1.

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIb:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIc:

and

HD is a moiety of Formula V:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIIc:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIId:

and

HD is a moiety of Formula V:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula IIId:

and

HD is a moiety of Formula VI:

In some embodiments of the compound of Formula I′,

TL is a moiety of Formula II:

wherein:

each of Q₁, Q₂, and Q₃ is independently nitrogen or —CR_(b)—, whereineach R_(b) is independently hydrogen, halogen, or lower alkyl;

R₁ is an optionally substituted alkyl, an optionally substitutednon-aromatic carbocyclic group, an optionally substituted aryl group, anoptionally substituted heterocycloalkyl group, an optionally substitutedheteroaryl group, an optionally substituted (carbocyclic)alkyl group, anoptionally substituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted C-carboxy or O-carboxy group, —CN, an optionallysubstituted carbamoyl group, or an optionally substituted carbamoylalkyl group, where the nitrogen of the carbamoyl or carbamoyl alkylgroup is optionally a heteroatom in a ring structure;

R₂ is halogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or —CN;

R₃ is hydrogen;

CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

HD is a moiety of Formula V:

wherein

R₉ is hydrogen, —CN, —NH₂, —C(R_(d))₂—S—R_(d), —C(R_(d))₂—S(═O)₂R_(a),or —C≡C—R_(d), wherein each R_(d) is independently hydrogen or loweralkyl; and

L_(a) is oxygen or —CH₂—.

In some embodiments of the compound of Formula I′, Q₁, Q₂, Q₃, and Q₄are —CR_(b)—, where each R_(b) is independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl. In some embodiments of the compound of Formula I′,Q₁, Q₂, and Q₃ are —CH—.

In some embodiments of the compound of Formula I′, Q₁ is —CH—, and Q₂and Q₃ are nitrogen. In some embodiments of the compound of Formula I′,Q₂ is —CH—, and Q₁ and Q₃ are nitrogen. In some embodiments of thecompound of Formula I′, Q₃ is —CH—, and Q₁ and Q₂ are nitrogen.

In some embodiments of the compound of Formula I′, Q₁ is nitrogen, andQ₂ and Q₃ are —CH—. In some embodiments of the compound of Formula I′,Q₂ is nitrogen, and Q₁ and Q₃ are —CH—. In some embodiments of thecompound of Formula I′, Q₃ is nitrogen, and Q₁ and Q₂ are —CH—.

In some embodiments of the compound of Formula I′, Q₄, Qs, and Q₆ are—CR_(b)—, where each R_(b) is independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl. In some embodiments of the compound of Formula I′,Q₄, Qs, and Q₆ are —CH—.

In some embodiments of the compound of Formula I′, Q₄ is —CH—, and Q₅and Q₆ are nitrogen. In some embodiments of the compound of Formula I′,Q₅ is —CH—, and Q₄ and Q₆ are nitrogen. In some embodiments of thecompound of Formula I′, Q₆ is —CH—, and Q₄ and Q₅ are nitrogen.

In some embodiments of the compound of Formula I′, Q₄ is nitrogen, andQ₅ and Q₆ are —CH—. In some embodiments of the compound of Formula I′,Q₅ is nitrogen, and Q₄ and Q₆ are —CH—. In some embodiments of thecompound of Formula I′, Q₆ is nitrogen, and Q₄ and Qs are —CH—.

In some embodiments of the compound of Formula I′, Q₄ is —CH— and Q₅ isnitrogen

In some embodiments of the compound of Formula I′, Q₅ and Q₆ arenitrogen.

In some embodiments of the compound of Formula I′, Q₅ is nitrogen and Q₈is —CH—.

In some embodiments of the compound of Formula I′, Q₅, Q₆, and Q₈ are—CR_(b)—, where each R_(b) is independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl. In some embodiments of the compound of Formula I′,Q₅, Q₆, and Q₈ are —CH—.

In some embodiments of the compound of Formula I′, Q₅ is —CH—, and Q₆and Q₈ are nitrogen. In some embodiments of the compound of Formula I′,Q₆ is —CH—, and Q₅ and Q₈ are nitrogen. In some embodiments of thecompound of Formula I′, Q₅ is —CH—, and Q₅ and Q₆ are nitrogen.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, anoptionally substituted alkyl, an optionally substituted non-aromaticcarbocyclic group, an optionally substituted aryl group, and anoptionally substituted C-carboxy group. In some embodiments of thecompound of Formula I′, the alkyl is selected from the group consistingof methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Insome embodiments of the compound of Formula I′, at least one carbon atomof the listed alkyl moieties is perfluorinated. In some embodiments ofthe compound of Formula I′, the alkyl is substituted with cycloalkyl oraryl. In some embodiments of the compound of Formula I′, the cycloalkylis selected from the group consisting of cyclopropyl, cyclopentyl, andcyclohexyl. In some embodiments of the compound of Formula I′, the arylis optionally substituted phenyl. In some embodiments of the compound ofFormula I′, the carbocyclic group is cyclohexane or cyclopentane. Insome embodiments of the compound of Formula I′, the aryl group isphenyl. In some embodiments of the compound of Formula I′, the C-carboxygroup is a moiety of formula —C(═O)—O—R, where R is selected from thegroup consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,and t-butyl.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, C₁-C₆alkyl, a non-aromatic C₃-C₁₂ carbocyclic group, a C₆-C₁₀ aryl group, a3- to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, a(carbocyclic)alkyl group, an aralkyl group, a (heterocycloalkyl)alkylgroup, a (heteroaryl)alkyl group, an amino group, a C-carboxy orO-carboxy group, —CN, or a carbamoyl group; and R₁ is optionallysubstituted with one to five R_(k) independently selected from the groupconsisting of hydroxy, halogen, —CN, amino, oxo, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is hydrogen. Insome embodiments of the compound of Formula I′, R₁ is —CN.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted C₁-C₆ alkyl. In some embodiments of the compound of FormulaI′, R₁ is C₁-C₆ alkyl optionally substituted with one to five R_(k)independently selected from the group consisting of hydroxy, halogen,—CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, R₁ is C₁-C₆ alkyl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted non-aromatic carbocyclic group. In some embodiments of thecompound of Formula I′, R₁ is a non-aromatic C₃-C₁₂ carbocyclic groupoptionally substituted with one to five R_(k) independently selectedfrom the group consisting of hydroxy, oxo, halogen, amino, O-carboxy,C-carboxy, C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted aryl group. In some embodiments of the compound of FormulaI′, R₁ is a C₆-C₁₀ aryl group optionally substituted with one to fiveR_(k) independently selected from the group consisting of hydroxy,halogen, —CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl,a 3- to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted heterocycloalkyl group. In some embodiments of the compoundof Formula I′, R₁ is a 3- to 6-membered heterocycloalkyl ring containingone to four ring heteroatoms independently selected from oxygen, sulfur,or nitrogen, wherein the heterocycloalkyl ring is optionally substitutedwith one to five R_(k) independently selected from the group consistingof hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted heteroaryl group. In some embodiments of the compound ofFormula I′, R₁ is a five- to ten-membered heteroaryl group containingone to four ring heteroatoms independently selected from oxygen, sulfur,or nitrogen, wherein the heteroaryl group is optionally substituted withone to five R_(k) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted (carbocyclic)alkyl group. In some embodiments of thecompound of Formula I′, R₁ is (cyclopentyl)C₁-C₆ alkyl,(cyclobutyl)C₁-C₆ alkyl, (cyclopentyl)C₁-C₆ alkyl, (cyclohexyl)C₁-C₆alkyl, (cycloheptyl)C₁-C₆ alkyl, (cyclooctyl)C₁-C₆ alkyl, or(cyclononyl)C₁-C₆ alkyl, and R₁ is optionally substituted with one tofive R_(k) independently selected from the group consisting of hydroxy,halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl,a 3- to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted aralkyl group. In some embodiments of the compound ofFormula I′, R₁ is a benzyl group optionally substituted with one to fiveR_(k) independently selected from the group consisting of hydroxy,halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl,a 3- to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted (heterocycloalkyl)alkyl group. In some embodiments of thecompound of Formula I, R₁ is a (heterocycloalkyl)alkyl group optionallysubstituted with one to five R_(k) independently selected from the groupconsisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted (heteroaryl)alkyl group. In some embodiments of the compoundof Formula I′, R₁ is a (heteroaryl)alkyl group optionally substitutedwith one to five R_(k) independently selected from the group consistingof hydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted amino group. In some embodiments of the compound of FormulaI′, R₁ is an amino group optionally substituted with one or twosubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, C₆-C₁₀ aryl,C-carboxy, C-amido, —(SO₂)(C₁-C₆ alkyl), —C(O)O(C₁-C₆ alkyl),—C(O)O(C₁-C₆ haloalkyl), —C(O)O(C₃-C₉ cycloalkyl), —C(O)O(3- to6-membered heterocycloalkyl), —C(O)O (five- to ten-membered heteroaryl),and —C(O)O(C₆-C₁₀ aryl). In some embodiments of the compound of FormulaI′, R₁ is —NR_(m)R_(n), wherein R_(m) and R_(n) are independentlyselected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₉cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, C₆-C₁₀ aryl, C-carboxy, C-amido, —(SO₂)(C₁-C₆ alkyl),—C(O)O(C₁-C₆ alkyl), —C(O)O(C₃-C₉ cycloalkyl), —C(O)O(3- to 6-memberedheterocycloalkyl), —C(O)O(five- to ten-membered heteroaryl), and—C(O)O(C₆-C₁₀ aryl); or R_(m) and R_(n) together with the nitrogen towhich they are attached form a 3- to 18-membered heterocycloalkyl ring;and R₁ is optionally substituted with one to five R_(k) independentlyselected from the group consisting of hydroxy, halogen, —CN, amino,C₁-C₆ alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted C-carboxy group. In some embodiments of the compound ofFormula I′, R₁ is —C(O)(C₁-C₆ alkyl), —C(O)(C₃-C₉ cycloalkyl), —C(O)(3-to 6-membered heterocycloalkyl), —C(O)(five- to ten-memberedheteroaryl), and —C(O)(C₆-C₁₀ aryl); and R₁ is optionally substitutedwith one to five R_(k) independently selected from the group consistingof hydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted O-carboxy group. In some embodiments of the compound ofFormula I′, R₁ is —OC(O)(C₁-C₆ alkyl), —OC(O)(C₃-C₉ cycloalkyl),—OC(O)(3- to 6-membered heterocycloalkyl), —OC(O)(five- to ten-memberedheteroaryl), and —OC(O)(C₆-C₁₀ aryl); and R₁ is optionally substitutedwith one to five R_(k) independently selected from the group consistingof hydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is an optionallysubstituted carbamoyl group. In some embodiments of the compound ofFormula I′, R₁ is —C(O)NR_(m)R_(n), wherein R_(m) and R_(n) areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl; or R_(m) and R_(n)together with the nitrogen to which they are attached form a 3- to18-membered heterocycloalkyl ring; and R₁ is optionally substituted withone to five R_(k) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substitutednon-aromatic C₃-C₁₂ carbocyclic group, an optionally substituted C₆-C₁₀aryl group, and an optionally substituted C-carboxy group.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, anoptionally substituted C₁-C₆ alkyl, an optionally substitutednon-aromatic C₃-C₁₂ carbocyclic group, an optionally substituted C₆-C₁₀aryl group, an optionally substituted C-carboxy group, and an optionallysubstituted carbamoyl group.

In some embodiments of the compound of Formula I′, R₁ is hydrogen; —CN;C₁-C₆ alkyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or —C(O)—R_(j); wherein R_(j) is—NR_(m)R_(n) or —OR_(m); R_(m) is hydrogen or C₁-C₆ alkyl; R_(n) isC₁-C₆ alkyl; or R_(m) and R_(n), together with the nitrogen to whichthey are attached, form a ring structure; and R₁ is optionallysubstituted with one to five R_(k) independently selected from hydroxy,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₆-C₁₀aralkoxy.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, —CN,C₁-C₆ alkyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or —C(O)—R_(j); wherein R_(j) is—NR_(m)R_(n) or —OR_(m); R_(m) is hydrogen or C₁-C₆ alkyl; R_(n) isC₁-C₆ alkyl; or R_(m) and R_(n), together with the nitrogen to whichthey are attached, form a ring structure; and R₁ is optionallysubstituted with one to three R_(k) independently selected from phenyland haloalkyl.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, —CN,C₁-C₆ alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl, or—C(O)—R_(j); wherein R_(j) is —NR_(m)R_(n) or —OR_(m); R_(m) is hydrogenor C₁-C₆ alkyl; R_(n) is C₁-C₆ alkyl; or R_(m) and R_(n), together withthe nitrogen to which they are attached, form1,2,3,4-tetrahydroisoquinoline; and R₁ is optionally substituted withone to three R_(k) independently selected from phenyl and haloalkyl.

In some embodiments of the compound of Formula I′, R₁ is hydrogen, —CN,C₁-C₆ alkyl, cyclopentyl, phenyl, (cyclopropyl)alkyl, benzyl,isopropylamino, or —C(O)—R_(j); wherein R_(j) is —NR_(m)R_(n) or—OR_(m); R_(m) is hydrogen or C₁-C₆ alkyl; R_(n) is C₁-C₆ alkyl; orR_(m) and R_(n), together with the nitrogen to which they are attached,form 1,2,3,4-tetrahydroisoquinoline; and R₁ is optionally substitutedwith one to three R_(k) independently selected from phenyl andhaloalkyl.

In some embodiments of the compound of Formula I′, R₂ is hydrogen,halogen, C₁-C₆ alkyl, C₃-C₉ cycloalkyl, or —CN; and R₂ is optionallysubstituted with one to five substituents independently selected fromthe group consisting of hydroxy, halogen, —CN, amino, C₁-C₆ alkyl,O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy,C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl group containingone to four ring heteroatoms independently selected from oxygen, sulfur,or nitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₂ is hydrogen. Insome embodiments of the compound of Formula I′, R₂ is halogen. In someembodiments of the compound of Formula I′, R₂ is —CN.

In some embodiments of the compound of Formula I′, R₂ is optionallysubstituted C₁-C₆ alkyl. In some embodiments of the compound of FormulaI′, R₂ is C₁-C₆ alkyl optionally substituted with one to fivesubstituents independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₈ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula I′, R₂ is optionallysubstituted C₃-C₉ cycloalkyl. In some embodiments of the compound ofFormula I′, R₂ is C₃-C₈ cycloalkyl optionally substituted with one tofive substituents independently selected from the group consisting ofhydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₂ isC₃-C₉ cycloalkyl optionally substituted with one to ten substituentsindependently selected from the group consisting of hydroxy, halogen,and C₁-C₆ alkoxy.

In some embodiments of the compound of Formula I′, R₂ is hydrogen oroptionally substituted C₁-C₆ alkyl. In some embodiments of the compoundof Formula I′, R₂ is selected from the group consisting of hydrogen,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl.

In some embodiments of the compound of Formula I′, R₂ is hydrogen;halogen; C₁-C₆ alkyl optionally substituted with one to fivesubstituents independently selected from the group consisting ofhydroxy, halogen, and C₁-C₆ alkoxy; C₃-C₉ cycloalkyl optionallysubstituted with one to ten substituents independently selected from thegroup consisting of hydroxy, halogen, and C₁-C₆ alkoxy; or —CN.

In some embodiments of the compound of Formula I′, R₃ is hydrogen. Insome embodiments of the compound of Formula I′, R₃ is lower alkyl.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, or anoptionally substituted (heterocycloalkyl)alkyl group.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl;C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a(heterocycloalkyl)alkyl group; and R₄ is optionally substituted with oneto five R_(g) independently selected from the group consisting ofhydroxy, halogen, CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, and C₆-C₁₀ aralkoxy, or two R_(g) together with the atoms towhich they are attached form an aromatic or non-aromatic 3- to6-membered ring, optionally containing one or two ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl;C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a(heterocycloalkyl)alkyl group; and R₄ is optionally substituted with oneto five R_(g) independently selected from the group consisting ofhydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀aralkoxy, or two R_(g) together with the atoms to which they areattached form a ring.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl;C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a 3- to6-membered heterocycloalkyl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen; a(carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkylgroup; and R₄ is optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀aralkoxy, or two R_(g) together with the atoms to which they areattached form an aromatic or non-aromatic 3- to 6-membered ring,optionally containing one or two ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl,C₂-C₁₀ alkenyl, a non-aromatic C₃-C₁₂ carbocyclic ring, a 3- to6-membered heterocycloalkyl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a(carbocyclic)alkyl group, an aralkyl group, or a (heterocycloalkyl)alkylgroup; and R₄ is optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl,C₂-C₁₀ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one,phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl,pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, a(cyclobutyl)alkyl group, a (cyclopentyl)alkyl group, a benzyl group, a(tetrahydrofuranyl)alkyl group, or a (tetrahydropyranyl)alkyl group; andR₄ is optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, CN, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀ aralkoxy, or twoR_(g) together with the atoms to which they are attached form anaromatic or non-aromatic 3- to 6-membered ring, optionally containingone or two ring heteroatoms independently selected from oxygen, sulfur,or nitrogen.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl,C₂-C₁₀ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, a (cyclobutyl)alkyl group, a(cyclopentyl)alkyl group, a benzyl group, a (tetrahydrofuranyl)alkylgroup, or a (tetrahydropyranyl)alkyl group; and R₄ is optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy,and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted alkyl. In some embodiments of the compound of Formula I′, R₄is an optionally substituted C₁-C₆ alkyl. In some embodiments of thecompound of Formula I′, R₄ is C₁-C₆ alkyl optionally substituted withone to five R_(g) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ isC₁-C₆ alkyl optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy. In some embodiments ofthe compound of Formula I′, R₄ is selected from the group consisting ofmethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. Insome embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl. Insome embodiments of the compound of Formula I′, R₄ is C₁-C₃ alkyl. Insome embodiments of the compound of Formula I′, R₄ is C₅-C₆ alkyl.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted alkenyl. In some embodiments of the compound of Formula I′,R₄ is an optionally substituted C₂-C₁₀ alkenyl. In some embodiments ofthe compound of Formula I′, R₄ is C₂-C₁₀ alkenyl optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ isC₂-C₁₀ alkenyl optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted non-aromatic carbocyclic group. In some embodiments of thecompound of Formula I′, R₄ is an optionally substituted non-aromaticC₃-C₁₂ carbocyclic group. In some embodiments of the compound of FormulaI′, R₄ is a non-aromatic C₃-C₁₂ carbocyclic group optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, oxo, halogen, CN, amino, O-carboxy, C-carboxy, C-amido,N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl, or two R_(g) together with the atoms to which they are attachedform an aromatic or non-aromatic 3- to 6-membered ring, optionallycontaining one or two ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is a non-aromatic C₃-C₁₂ carbocyclic group optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl. In some embodiments of the compound of Formula I′, R₄ is anon-aromatic C₃-C₁₂ carbocyclic group optionally substituted with one tofive R_(g) independently selected from the group consisting of hydroxy,halogen, CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,and C₆-C₁₀ aralkoxy, or two R_(g) together with the atoms to which theyare attached form an aromatic or non-aromatic 3- to 6-membered ring,optionally containing one or two ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is a non-aromatic C₃-C₁₂ carbocyclic group optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy,and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted heterocycloalkyl group. In some embodiments of the compoundof Formula I′, R₄ is an optionally substituted 3- to 6-memberedheterocycloalkyl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen; wherein theheterocycloalkyl ring is optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, oxo,halogen, CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl, or two R_(g) together withthe atoms to which they are attached form an aromatic or non-aromatic 3-to 6-membered ring, optionally containing one or two ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen. In someembodiments of the compound of Formula I′, R₄ is an optionallysubstituted 3- to 6-membered heterocycloalkyl ring containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen; wherein the heterocycloalkyl ring is optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, R₄ is an optionally substituted 3- to 6-memberedheterocycloalkyl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen; wherein theheterocycloalkyl ring is optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,CN, oxo, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, andC₆-C₁₀ aralkoxy. In some embodiments of the compound of Formula I′, R₄is an optionally substituted 3- to 6-membered heterocycloalkyl ringcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen; wherein the heterocycloalkyl ring isoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted (carbocyclic)alkyl group. In some embodiments of thecompound of Formula I′, R₄ is (cyclopropyl)C₁-C₆ alkyl,(cyclobutyl)C₁-C₆ alkyl, (cyclopentyl)C₁-C₆ alkyl, (cyclohexyl)C₁-C₆alkyl, (cycloheptyl)C₁-C₆ alkyl, (cyclooctyl)C₁-C₆ alkyl, or(cyclononyl)C₁-C₆ alkyl, and R₄ is optionally substituted with one tofive R_(g) independently selected from the group consisting of hydroxy,halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, oxo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl, or two R_(g) togetherwith the atoms to which they are attached form an aromatic ornon-aromatic 3- to 6-membered ring, optionally containing one or tworing heteroatoms independently selected from oxygen, sulfur, ornitrogen. In some embodiments of the compound of Formula I′, R₄ is(cyclopropyl)C₁-C₆ alkyl, (cyclobutyl)C₁-C₆ alkyl, (cyclopentyl)C₁-C₆alkyl, (cyclohexyl)C₁-C₆ alkyl, (cycloheptyl)C₁-C₆ alkyl,(cyclooctyl)C₁-C₆ alkyl, or (cyclononyl)C₁-C₆ alkyl, and R₄ isoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, —CN, amino, O-carboxy,C-carboxy, C-amido, N-amido, oxo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ is(cyclopropyl)C₁-C₆ alkyl, (cyclobutyl)C₁-C₆ alkyl, (cyclopentyl)C₁-C₆alkyl, (cyclohexyl)C₁-C₆ alkyl, (cycloheptyl)C₁-C₆ alkyl,(cyclooctyl)C₁-C₆ alkyl, or (cyclononyl)C₁-C₆ alkyl, and R₄ isoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted aralkyl group. In some embodiments of the compound ofFormula I′, R₄ is a benzyl group optionally substituted with one to fiveR_(g) independently selected from the group consisting of hydroxy,halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl, or two R_(g) togetherwith the atoms to which they are attached form an aromatic ornon-aromatic 3- to 6-membered ring, optionally containing one or tworing heteroatoms independently selected from oxygen, sulfur, ornitrogen. In some embodiments of the compound of Formula I′, R₄ is abenzyl group optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, —CN, amino,O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ is abenzyl group optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, CN, C₁-C₆ alkyl,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀ aralkoxy. Insome embodiments of the compound of Formula I′, R₄ is a benzyl groupoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl,C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted (heterocycloalkyl)alkyl group. In some embodiments of thecompound of Formula I′, R₄ is a (heterocycloalkyl)alkyl group optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, oxo, halogen, amino, CN, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl, or two R_(g) together with the atoms to which they areattached form an aromatic or non-aromatic 3- to 6-membered ring,optionally containing one or two ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is a (heterocycloalkyl)alkyl group optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, oxo, halogen, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, R₄ is a (heterocycloalkyl)alkyl group optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy,and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted (heteroaryl)alkyl group. In some embodiments of the compoundof Formula I′, R₄ is a (heteroaryl)alkyl group optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl, or two R_(g) together withthe atoms to which they are attached form an aromatic or non-aromatic 3-to 6-membered ring, optionally containing one or two ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen. In someembodiments of the compound of Formula I′, R₄ is a (heteroaryl)alkylgroup optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, —CN, amino,O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ is a(heteroaryl)alkyl group optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀aralkoxy. In some embodiments of the compound of Formula I′, R₄ is a(heteroaryl)alkyl group optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is a C₆-C₁₀ arylgroup or a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; and R₄ is optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀aralkoxy, or two R_(g) together with the atoms to which they areattached form an aromatic or non-aromatic 3- to 6-membered ring,optionally containing one or two ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is a C₆-C₁₀ aryl group or a five- to ten-memberedheteroaryl ring containing one to four ring heteroatoms independentlyselected from oxygen, sulfur, or nitrogen; and R₄ is optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy,and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted C₆-C₁₀ aryl group. In some embodiments of the compound ofFormula I′, R₄ is a C₆-C₁₀ aryl group optionally substituted with one tofive R_(g) independently selected from the group consisting of hydroxy,halogen, —CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl, or two R_(g) togetherwith the atoms to which they are attached form an aromatic ornon-aromatic 3- to 6-membered ring, optionally containing one or tworing heteroatoms independently selected from oxygen, sulfur, ornitrogen. In some embodiments of the compound of Formula I′, R₄ is aC₆-C₁₀ aryl group optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,—CN, O-carboxy, C-carboxy, C-amido, N-amido, amino, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl,a 3- to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₄ is aC₆-C₁₀ aryl group optionally substituted with one to five R_(g)independently selected from the group consisting of hydroxy, halogen,CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀aralkoxy, or two R_(g) together with the atoms to which they areattached form an aromatic or non-aromatic 3- to 6-membered ring,optionally containing one or two ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is a C₆-C₁₀ aryl group optionally substituted with one tofive R_(g) independently selected from the group consisting of hydroxy,halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is benzeneoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, CN, C₁-C₆ alkyl, C₁-C₆alkoxy, and C₁-C₆ haloalkoxy, or two R_(g) together with the atoms towhich they are attached form an aromatic or non-aromatic 3- to6-membered ring, optionally containing one or two ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen. In someembodiments of the compound of Formula I′, R₄ is benzene optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy, or twoR_(g) together with the atoms to which they are attached form a ring.

In some embodiments of the compound of Formula I′, R₄ is naphthaleneoptionally substituted with one to five R_(g) independently selectedfrom the group consisting of hydroxy, halogen, C₁-C₆ alkyl, and C₁-C₆alkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted heteroaryl group. In some embodiments of the compound ofFormula I′, R₄ is five- to ten-membered heteroaryl ring containing oneto four ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, wherein the heteroaryl ring is optionally substituted with oneto five R_(g) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl, or two R_(g) together with the atoms to which they are attachedform an aromatic or non-aromatic 3- to 6-membered ring, optionallycontaining one or two ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen. In some embodiments of the compound ofFormula I′, R₄ is five- to ten-membered heteroaryl ring containing oneto four ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, wherein the heteroaryl ring is optionally substituted with oneto five R_(g) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, R₄ is five- to ten-membered heteroaryl ringcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, and C₆-C₁₀ aralkoxy. In some embodiments ofthe compound of Formula I′, R₄ is five- to ten-membered heteroaryl ringcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, wherein the heteroaryl ring is optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy,and C₆-C₁₀ aralkoxy.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted amino group. In some embodiments of the compound of FormulaI′, R₄ is an amino group optionally substituted with one or twosubstituents independently selected from the group consisting of C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, C₆-C₁₀ aryl,C-carboxy, C-amido, —(SO₂)(C₁-C₆ alkyl), —C(O)O(C₁-C₆ alkyl),—C(O)O(C₁-C₆ haloalkyl), —C(O)O(C₃-C₉ cycloalkyl), —C(O)O(3- to6-membered heterocycloalkyl), —C(O)O(five- to ten-membered heteroaryl),and —C(O)O(C₆-C₁₀ aryl). In some embodiments of the compound of FormulaI′, R₄ is —NR_(m)R_(n), wherein R_(m) and R_(n) are independentlyselected from the group consisting of hydrogen, C₁-C₆ alkyl, C₃-C₉cycloalkyl, a 3- to 6-membered heterocycloalkyl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, C₆-C₁₀ aryl, C-carboxy, C-amido, —(SO₂)(C₁-C₆ alkyl),—C(O)O(C₁-C₆ alkyl), —C(O)O(C₃-C₉ cycloalkyl), —C(O)O(3- to 6-memberedheterocycloalkyl), —C(O)O(five- to ten-membered heteroaryl), and—C(O)O(C₆-C₁₀ aryl); or R_(m) and R_(n) together with the nitrogen towhich they are attached form a 3- to 18-membered heterocycloalkyl ring;and R₁ is optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, —CN, amino,C₁-C₆ alkyl, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted sulfamoyl group. In some embodiments of the compound ofFormula I′, R₄ is —SO₂NR_(m)R_(n), wherein R_(m) and R_(a) areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl; or R_(m) and R_(n)together with the nitrogen to which they are attached form a 3- to18-membered heterocycloalkyl ring; and R₁ is optionally substituted withone to five R_(g) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted carbamoyl group. In some embodiments of the compound ofFormula I′, R₄ is —C(O)NR_(m)R_(n), wherein R_(m) and R_(n) areindependently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl; or R_(m) and R_(n)together with the nitrogen to which they are attached form a 3- to18-membered heterocycloalkyl ring; and R₁ is optionally substituted withone to five R_(g) independently selected from the group consisting ofhydroxy, halogen, —CN, amino, C₁-C₆ alkyl, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₅ is hydroxy. Insome embodiments of the compound of Formula I′, R₅ is NH₂.

In some embodiments of the compound of Formula I′, R₅ is alkylamino. Insome embodiments of the compound of Formula I′, R₅ is —NR_(u)R_(v),wherein R_(u) is hydrogen or C₁-C₆ alkyl and R_(v) is C₁-C₁₂ alkyloptionally substituted with one to five substituents independentlyselected from the group consisting of hydroxy, halogen, —CN, amino,O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy,C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl group containingone to four ring heteroatoms independently selected from oxygen, sulfur,or nitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₅ is alkanoylamino.In some embodiments of the compound of Formula I′, R₅ is—NR_(u)C(O)R_(v), wherein R_(u) is hydrogen or C₁-C₆ alkyl and R_(v) isC₁-C₁₂ alkyl optionally substituted with one to five substituentsindependently selected from the group consisting of hydroxy, halogen,—CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₅ isalkylsulfonylamino. In some embodiments of the compound of Formula I′,R₅ is —NR_(u)SO₂R_(v), wherein R_(u) is hydrogen or C₁-C₆ alkyl andR_(v) is C₁-C₁₂ alkyl optionally substituted with one to fivesubstituents independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula I′, R₅ is hydroxy or NH₂.In some embodiments of the compound of Formula I′, R₅ is hydroxy, NH₂,C₁-C₆ alkylamino, C₁-C₆ alkanoylamino, or C₁-C₆ alkylsulfonylamino.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form afive- or six-membered optionally substituted non-aromatic C₃-C₁₂carbocyclic group, optionally substituted C₆-C₁₀ aryl group, optionallysubstituted heterocyclic group, or optionally substituted heteroarylgroup. In some embodiments of the compound of Formula I′, R₄ and R₅taken together along with the carbon atoms to which they are attachedform a five- or six-membered non-aromatic C₃-C₁₂ carbocyclic group,C₆-C₁₀ aryl group, 4- to 6-membered heterocycloalkyl group containingone to four ring heteroatoms independently selected from oxygen, sulfur,or nitrogen, a five- to ten-membered heteroaryl group containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, wherein the carbocyclic group, the aryl group, theheterocycloalkyl group, and the heteroaryl group are optionallysubstituted with one to five substituents independently selected fromthe group consisting of hydroxy, halogen, —CN, amino, O-carboxy,C-carboxy, C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, a five- to ten-membered heteroarylgroup containing one to four ring heteroatoms independently selectedfrom oxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form aseven to eleven membered, optionally substituted spirocyclic ring or aseven to eleven membered, optionally substituted spiro-heterocyclicring. In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form aseven to eleven membered, spirocyclic ring or a seven to eleven memberedspiro-heterocyclic ring; and the spirocyclic ring and spiro-heterocyclicring are optionally substituted with one to five substituentsindependently selected from the group consisting of hydroxy, halogen,—CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form afive- or six-membered optionally substituted non-aromatic carbocyclicgroup, optionally substituted aryl group, optionally substitutedheterocycloalkyl group, or optionally substituted heteroaryl group.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form afive- or six-membered non-aromatic carbocyclic group; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; or a five- to ten-membered heteroaryl ring containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen; and wherein the carbocyclic group, the aryl group, theheterocycloalkyl ring, and the heteroaryl ring are optionallysubstituted with one to five R_(g) independently selected from the groupconsisting of hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, and oxo,and/or optionally two R_(g) together with the atom(s) to which they areattached form a 3- to 6-membered carbocyclic group.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form a3- to 6-membered heterocycloalkyl ring containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen; andwherein the heterocycloalkyl ring is optionally substituted with one tofive R_(g) independently selected from the group consisting of C₁-C₆alkyl and oxo, and/or optionally two R_(g) together with the atom(s) towhich they are attached form a 3- to 6-membered non-aromatic carbocyclicgroup.

In some embodiments of the compound of Formula I′, R₄ and R₅ takentogether along with the carbon atoms to which they are attached form apyrrolidine optionally substituted with one to five R_(g) independentlyselected from the group consisting of C₁-C₆ alkyl and oxo, and/oroptionally two R_(g) together with the atom(s) to which they areattached form a 3- to 6-membered non-aromatic carbocyclic group.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIIaa:

wherein each R_(g) is independently C₁-C₆ alkyl; or the two R_(g)together with the atom to which they are attached form an alkeneoptionally substituted with C₁-C₆ alkyl; or the two R_(g) together withthe atom to which they are attached form a 3- to 6-membered non-aromaticcarbocyclic group. In some embodiments of the compound of Formula I′,the two R_(g) together with the atom to which they are attached form acyclopropyl group, a cyclobutyl group, a cyclopentyl group, or acyclohexyl group.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIIaa:

wherein each R_(g) is independently C₁-C₆ alkyl or the two R_(g)together with the atom(s) to which they are attached form a 3- to6-membered non-aromatic carbocyclic group. In some embodiments of thecompound of Formula I′, the two R_(g) together with the atom to whichthey are attached form a cyclopentyl group or a cyclohexyl group.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIIab:

wherein R_(g) is C₁-C₆ alkyl. In some embodiments of the compound ofFormula I′, R_(g) is isopropyl.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIIac:

wherein R_(g) is C₁-C₆ alkyl. In some embodiments of the compound ofFormula I′, R_(g) is methyl.

In some embodiments of the compound of Formula I′, TL is a moiety ofFormula IIIad:

wherein each R_(g) is independently hydrogen or C₁-C₆ alkyl.

In some embodiments of the compound of Formula I′, R₄ is an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocycloalkyl group, anoptionally substituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, or an optionally substitutedcarbamoyl group; and R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, oralkylsulfonylamino.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl;C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring, a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; a (heteroaryl)alkyl group; or—C(O)NR_(m)R_(n);

R_(m) and R_(n) are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkoxy, a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or a (heteroaryl)alkyl group; or R_(m)and R_(n) together with the nitrogen to which they are attached form a3- to 18-membered heterocycloalkyl ring;

and R₄ is optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino.

In some embodiments of the compound of Formula I′, R₄ is C₁-C₆ alkyl;C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring, a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; a (heteroaryl)alkyl group; or—C(O)NR_(m)R_(n);

R_(m) and R_(n) are independently selected from the group consisting ofhydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkoxy, a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or a (heteroaryl)alkyl group; or R_(m)and R_(n) together with the nitrogen to which they are attached form a3- to 18-membered heterocycloalkyl ring;

and R₄ is optionally substituted with one to five R_(g) independentlyselected from the group consisting of hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, and C₆-C₁₀ aralkoxy; and

R₅ is hydroxy.

In some embodiments of the compound of Formula I′, Alk is hydrogen oroptionally substituted C₁-C₆ alkyl. In some embodiments of the compoundof Formula I′, Alk is hydrogen or C₁-C₆ alkyl optionally substitutedwith one to five substituents independently selected from the groupconsisting of hydroxy, halogen, —CN, amino, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, Alk ishydrogen. In some embodiments of the compound of Formula I′, Alk isC₁-C₆ alkyl optionally substituted with one to five substituentsindependently selected from the group consisting of hydroxy, halogen,—CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, Alk is C₁-C₆ alkyl optionally substituted withone to five substituents independently selected from the groupconsisting of hydroxy, halogen, and C₁-C₆ alkoxy.

In some embodiments of the compound of Formula I′, R₁₁ is an aryl groupoptionally substituted with one to five substituents independentlyselected from lower alkyl, alkoxy, haloalkoxy, halogen, and C₃-C₉cycloalkyl; or a heteroaryl group optionally substituted with one tofive substituents independently selected from lower alkyl, alkoxy,haloalkoxy, halogen, and cycloalkyl; or a bicyclic ring systemcontaining either aromatic or saturated rings; or a bicyclicheterocyclic containing either aromatic or saturated ring systems. Insome embodiments of the compound of Formula I′, R₁₁ is an aryl groupoptionally substituted with one to five substituents independentlyselected from lower alkyl, halogen, and C₃-C₉ cycloalkyl; or a bicyclicring system containing either aromatic or saturated rings; or a bicyclicheterocyclic containing either aromatic or saturated ring systems. Insome embodiments of the compound of Formula I′, R₁₁ is a C₆-C₁₀ arylgroup optionally substituted with one to five substituents independentlyselected from lower alkyl, alkoxy, haloalkoxy, halogen, and C₃-C₉cycloalkyl; or a five- to ten-membered heteroaryl group containing oneto four ring heteroatoms independently selected from oxygen, sulfur, ornitrogen, wherein the heteroaryl group is optionally substituted withone to five substituents independently selected from lower alkyl,alkoxy, haloalkoxy, halogen, and C₃-C₉ cycloalkyl; or a 7- to12-membered bicyclic ring system containing either aromatic or saturatedrings; or a 7- to 12-membered bicyclic heterocyclic containing eitheraromatic or saturated ring systems. In some embodiments of the compoundof Formula I′, R₁ is a C₆-C₁₀ aryl group optionally substituted with oneto five substituents independently selected from lower alkyl, halogen,and C₃-C₉ cycloalkyl; or a 7- to 12-membered bicyclic ring systemcontaining either aromatic or saturated rings; or a 7- to 12-memberedbicyclic heterocyclic containing either aromatic or saturated ringsystems. In some embodiments of the compound of Formula I′, R₁₁ is aC₆-C₁₀ aryl group optionally substituted with one to five substituentsindependently selected from lower alkyl, alkoxy, haloalkoxy, halogen,and C₃-C₉ cycloalkyl. In some embodiments of the compound of Formula I′,R₁₁ is a C₆-C₁₀ aryl group optionally substituted with one to fivesubstituents independently selected from lower alkyl, halogen, and C₃-C₉cycloalkyl. In some embodiments of the compound of Formula I′, R₁₁ afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen,wherein the heteroaryl group is optionally substituted with one to fivesubstituents independently selected from lower alkyl, alkoxy,haloalkoxy, halogen, and C₃-C₉ cycloalkyl. In some embodiments of thecompound of Formula I′, R₁₁ is a 7- to 12-membered bicyclic ring systemcontaining either aromatic or saturated rings. In some embodiments ofthe compound of Formula I′, R₁₁ is a 7- to 12-membered bicyclicheterocyclic containing either aromatic or saturated ring systems. Insome embodiments of the compound of Formula I′, R₁₁ is a benzeneoptionally substituted with one to five substituents independentlyselected from C₁-C₅ alkyl, C₁-C₅ alkoxy, C₁-C₅ haloalkoxy, halogen, andC₃-C₉ cycloalkyl; pyridine optionally substituted with C₁-C₅ alkyl;cinnoline; isoquinoline; quinoline; pyrazolo[1,5-a]pyridine;imidazo[1,5-a]pyridine; benzo[b]thiophene; chromane;1,2,3,4-tetrahydronaphthalene; or naphthalene. In some embodiments ofthe compound of Formula I′, R₁₁ is a benzene optionally substituted withone to five substituents independently selected from C₁-C₅ alkyl,halogen, and C₃-C₉ cycloalkyl; 1,2,3,4-tetrahydronaphthalene; ornaphthalene.

In some embodiments of the compound of Formula I′, each of R₆ and R₇ isindependently halogen or C₁-C₅ alkyl optionally substituted with one tofive substituents independently selected from hydroxy, halogen, andC₁-C₆ alkoxy; and R₈ is hydrogen; or R₆ is halogen or C₁-C₅ alkyloptionally substituted with one to five substituents independentlyselected from hydroxy, halogen, and C₁-C₆ alkoxy; and R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a4-, 5- or 6-membered carbocyclic ring.

In some embodiments of the compound of Formula I′, each of R₆ and R₇ isindependently chlorine, bromine, and iodine. In some embodiments of thecompound of Formula I′, each of R₆ and R₇ is independently —CN, anoptionally substituted lower alkyl or an optionally substituted loweralkoxy, where the lower alkyl and the alkyl group of the lower alkoxy iseach independently selected from methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, and t-butyl. In some embodiments of the compound ofFormula I′, R₆ and R₇ are the same. In some embodiments of the compoundof Formula I′, each of R₆ and R₇ is independently chlorine or methyl. Insome embodiments of the compound of Formula I′, R₆ is Cl, R₇ is Cl, andR₈ is hydrogen. In some embodiments of the compound of Formula I′, R₆ isCl, R₇ is Cl, and R₈ is methyl. In some embodiments of the compound ofFormula I′, R₆ is halogen and R₇ and R₈ taken together, along with thecarbon atoms to which they are attached, form a 4-membered carbocyclicring.

In some embodiments of the compound of Formula I′, R₈ is hydrogen. Insome embodiments of the compound of Formula I′, R₈ is optionallysubstituted lower alkyl. In some embodiments of the compound of FormulaI′, R₈ is lower alkyl optionally substituted with one to fivesubstituents selected from the group consisting of hydroxy, halogen,amino, —CN, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₃-C₅cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing oneheteroatom independently selected from oxygen, sulfur, or nitrogen. Insome embodiments of the compound of Formula I′, R₈ is optionallysubstituted lower alkoxy. In some embodiments of the compound of FormulaI′, R₈ is lower alkoxy optionally substituted with one to fivesubstituents selected from the group consisting of hydroxy, halogen,amino, —CN, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₃-C₅cycloalkyl, a 3- to 5-membered heterocycloalkyl group containing oneheteroatom independently selected from oxygen, sulfur, or nitrogen. Insome embodiments of the compound of Formula I′, R₈ is cyano. In someembodiments of the compound of Formula I′, R₈ is halogen.

In some embodiments of the compound of Formula I′, R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a4-, 5- or 6-membered non-aromatic carbocyclic, a 3- to 5-memberedheterocycloalkyl, a C₆-C₁₀ aryl, or a five- to ten-membered heteroarylring.

In some embodiments of the compound of Formula I′, Q₇ is nitrogen. Insome embodiments of the compound of Formula I′, Q₇ is —CR_(c)—. In someembodiments of the compound of Formula I′, R_(c) is hydrogen. In someembodiments of the compound of Formula I′, R_(e) is halogen. In someembodiments of the compound of Formula I′, R_(c) is lower alkyl. In someembodiments of the compound of Formula I′, R_(e) is hydrogen or methyl.In some embodiments of the compound of Formula I′, Q₇ is —CH—.

In some embodiments of the compound of Formula I′, R₉ is hydrogen,—(C(R_(a))₂)_(n)—N(R_(a))₂, —(C(R_(a))₂)_(n)—CN, or—(C(R_(a))₂)_(n)—C≡C—R_(a). In some embodiments of the compound ofFormula I′, R₉ is hydrogen, —(CH₂)_(n)—N(R_(a))₂, —(CH₂)_(n)—CN, or—(CH₂)_(n)—C≡C—R_(d). In some embodiments of the compound of Formula I′,R₉ is selected from hydrogen, —N(R_(d))₂, —CN, or —C≡C—R_(d). In someembodiments of the compound of Formula I′, R₉ is selected from hydrogen,—NH₂, —CN, or —C≡CH.

In some embodiments of the compound of Formula I′, R₉ is hydrogen. Insome embodiments of the compound of Formula I′, R₉ is—(C(R_(a))₂)_(n)—C(R_(a))₃. In some embodiments of the compound ofFormula I′, R₉ is —(C(R_(d))₂)_(n)—OR_(d). In some embodiments of thecompound of Formula I′, R₉ is —(C(R_(d))₂)_(n)—N(R_(d))₂. In someembodiments of the compound of Formula I′, R₉ is —NH₂. In someembodiments of the compound of Formula I′, R₉ is—(C(R_(a))₂)_(n)—S(═O)_(q)R_(a). In some embodiments of the compound ofFormula I′, R₉ is —(C(R_(a))₂)_(n)—CN. In some embodiments of thecompound of Formula I′, R₉ is —CN. In some embodiments of the compoundof Formula I′, R₉ is —(C(R_(d))₂)_(n)—C≡C—R_(d). In some embodiments ofthe compound of Formula I′, R₉ is —C≡CH. In some embodiments of thecompound of Formula I′, R₉ is —(C(R_(a))₂)_(n)—C(═O)—OR_(d). In someembodiments of the compound of Formula I′, R₉ is —(C(R_(a))₂)_(n)—HeAr.In some embodiments of the compound of Formula I′, R₉ is—(C(R_(d))₂)_(n)—C(═O)—N(R_(d))₂.

In some embodiments of the compound of Formula I′, each R_(d) isindependently hydrogen or lower alkyl optionally substituted with one tofive substituents independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl. In some embodiments of the compound of Formula I′, each R_(d) ishydrogen. In some embodiments of the compound of Formula I′, each R_(d)is independently lower alkyl optionally substituted with one to fivesubstituents independently selected from the group consisting ofhydroxy, halogen, —CN, amino, O-carboxy, C-carboxy, C-amido, N-amido,C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-memberedheterocycloalkyl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, a five- toten-membered heteroaryl group containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula I′, q is 0. In someembodiments of the compound of Formula I′, q is 1. In some embodimentsof the compound of Formula I′, q is 2.

In some embodiments of the compound of Formula I′, n is 0. In someembodiments of the compound of Formula I′, n is 1. In some embodimentsof the compound of Formula I′, n is 2. In some embodiments of thecompound of Formula I′, n is 3. In some embodiments of the compound ofFormula I′, n is 4. In some embodiments of the compound of Formula I′, nis 5.

In some embodiments of the compound of Formula I′, HeAr is a 5- or6-membered heteroaryl group containing one to three ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen.

In some embodiments of the compound of Formula I′, R₁₀ is hydrogen or—C(R_(e))₃, wherein each R_(e) is independently hydrogen, halogen, orlower alkyl optionally substituted with one to five substituentsindependently selected from the group consisting of hydroxy, halogen,—CN, amino, O-carboxy, C-carboxy, C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀aralkoxy, C₃-C₉ cycloalkyl, a 3- to 6-membered heterocycloalkyl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, a five- to ten-membered heteroaryl groupcontaining one to four ring heteroatoms independently selected fromoxygen, sulfur, or nitrogen, and C₆-C₁₀ aryl. In some embodiments of thecompound of Formula I′, R₁₀ is hydrogen. In some embodiments of thecompound of Formula I′, R₁₀ is —C(R_(e))₃, wherein each R_(e) isindependently hydrogen, halogen, or lower alkyl optionally substitutedwith one to five substituents independently selected from the groupconsisting of hydroxy, halogen, —CN, amino, O-carboxy, C-carboxy,C-amido, N-amido, C₁-C₆ alkoxy, C₆-C₁₀ aralkoxy, C₃-C₉ cycloalkyl, a 3-to 6-membered heterocycloalkyl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, afive- to ten-membered heteroaryl group containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen, andC₆-C₁₀ aryl. In some embodiments of the compound of Formula I′, R₁₀ is—C(R_(e))₃, wherein each R_(e) is independently hydrogen, halogen, orlower alkyl. In some embodiments of the compound of Formula I′, R₁₀ ishydrogen, —CHF₂, —CH₃, or ethyl.

In some embodiments of the compound of Formula I′, L_(a) is a bond;—(C(R_(a))₂)_(z)—; oxygen; sulfur; or —NR_(a)—. In some embodiments ofthe compound of Formula I′, L_(a) is a bond. In some embodiments of thecompound of Formula I′, L_(a) is —(C(R_(a))₂)_(z)—. In some embodimentsof the compound of Formula I′, L_(a) is —CH₂—. In some embodiments ofthe compound of Formula I′, L_(a) is oxygen. In some embodiments of thecompound of Formula I′, L_(a) is sulfur. In some embodiments of thecompound of Formula I′, L_(a) is —NR_(a)—. In some embodiments of thecompound of Formula I′, each R_(a) is hydrogen. In some embodiments ofthe compound of Formula I′, each R_(a) is independently lower alkyl. Insome embodiments of the compound of Formula I′, each R_(a) isindependently a hydrogen or lower alkyl.

In some embodiments of the compound of Formula I′, z is 0. In someembodiments of the compound of Formula I′, z is 1. In some embodimentsof the compound of Formula I′, z is 2. In some embodiments of thecompound of Formula I′, z is 3. In some embodiments of the compound ofFormula I′, z is 4. In some embodiments of the compound of Formula I′, zis 5.

In another aspect, disclosed herein is a compound selected from thegroup consisting of:

Synthesis of the Compounds

The presently disclosed compounds were synthesized using the generalsynthetic procedures set forth in Schemes 1-10 below. The carrying outof each individual illustrated step is within the skill of an ordinaryartisan, who also knows how to modify the synthetic procedures of thebelow schemes to synthesize the full scope of the compounds disclosedherein. The synthetic procedure for individual compounds is provided inthe Examples section, below.

As described in Scheme 1, an aromatic amine compound of Formula S-II istransformed to an aza-uracil compound of Formula S-III, first bygenerating the corresponding diazonium salt, followed by reaction withan N-(2-cyanoacetyl)-carbamate, and finally cyclization, resulting inthe formation of a compound of Formula S-III. Next the nitrile ofFormula S-III is hydrolyzed to a carboxylic acid compound of FormulaS-IV. The compound of Formula S-IV is then reacted withdiphenylphosphoryl azide (DPPA), resulting in the formation of acompound of Formula S-V. Finally, the compound of Formula S-V isdeprotected.

As described in Scheme 2, the aromatic amine compound of Formula S-IIcan be converted to a boronic acid compound of Formula S-VII, first bygeneration of the diazonium salt, followed by reaction withtetrahydroxydiborane. The corresponding boronic acid is then coupledwith a suitably protected (with protecting group ‘PG’) bromo-azauracilcompound of Formula Int-I. The resulting bromide compound of FormulaS-VIII is then further transformed, either by a substitution reaction,or by transition metal catalyzed transformations as exemplified in theExamples section, below. Removal of the protecting group ‘PG’ results ina compound of Formula S-X.

The synthesis of an aromatic amine compound of Formula S-XIV isdescribed in Scheme 3. A compound of Formula S-XI is reacted with acompound of Formula S-XII, (‘X’ represents a halogen like F or Cl),followed by protection with a protecting group ‘PG’, resulting in acompound of Formula S-XIII. Reduction of the nitro functionality of thecompound of Formula S-XIII results in the formation of an aromatic aminecompound of Formula S-XIV.

Scheme 4 describes the synthesis of a compound of Formula S-XIX. Atransmetalation reaction of a compound of Formula S-XVI (‘X’ in thestructure represents a halogen, e.g., Br or I) is followed by anaddition to the aldehyde of general Formula S-XV affording the alcoholcompound of Formula S-XVII, which is then reduced to a compound ofFormula S-XVIII. Deprotection of PG2 of the compound of Formula S-XVIIIresults in the formation of a compound of Formula S-XIX.

As described in Scheme 5, a compound of Formula S-XX is obtained bycoupling a compound of Formula S-VII with a bromide compound of FormulaInt-II.

Scheme 6a depicts an alternative synthesis of the compounds of thegeneral Formula S-XIX. A compound of Formula S-XXI (wherein thestructure represents a halogen, e.g., C₁, Br or I) is coupled with acompound of Formula S-XXII in a Suzuki type coupling, resulting in theformation of a compound of Formula S-XXIII. The protecting group PG3,for example a benzyl moiety, can then be removed resulting in a compoundof Formula S-XXIV. The resulting phenol functionality can then bereplaced with a triflate group, resulting in a compound of generalFormula S-XXV. The —OTf group can then be replaced with a —NH₂ moietyvia a transition metal catalyzed reaction, such as a Buchwald coupling,for example with t-Butyl carbamate or benzophenone imine, followed bydeprotection, resulting in a compound of general Formula S-XIX. Themethod described in Scheme 6a could also apply when an indazolehalogenide is used as the starting material instead of S-XXI.Alternatively, the indazole halogenide may undergo lithium-halogenexchange. The resulting aryl lithium species could react with analdehyde of type S-XXVIII to form compounds of formula S-XXIX. Furtherelaboration of structures of formula S—XXIX are described in Scheme 7.

Scheme 6b depicts the synthesis of a compound of formula S—XXII from acompound of formula S-XXVI in a Suzuki reaction with4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane.

Scheme 7 describes the synthesis of a compound of Formula S-XXXI. Atransmetalation reaction of a compound of Formula S-XXVII (‘X’ in thestructure represents a halogen, e.g., Br or I) is followed by anaddition to the aldehyde of general formula S-XXVIII affording thealcohol compound of Formula S-XXIX, which is then reduced to a compoundof Formula S-XXX. Deprotection of PG2 of the compound of Formula S-XXXresults in the formation of a compound of Formula S-XXXI.

Scheme 8 describes the general synthesis of compounds of Formula S-XXIand products thereof. When R₁, for example, is hydrogen, and Y ishydrogen, then R₁ can be transformed to the corresponding acyl group viathe acid chloride and a Lewis acid (e.g. InBr3) in a non-polar, aproticsolvent (e.g. dichloroethane). The newly formed ketone group can bepartially reduced to the alcohol or fully reduced to the correspondingalkane. Further transformations of a ketone group are evident to thoseskilled in the art. In a second example, where R₁ is hydrogen, and Y isan appropriate protecting group (e.g. tosyl) then R₁ can be converted toiodide via an iodinating agent (e.g. NIS) using available literatureprocedures.

Scheme 9 describes the general synthesis of compounds of FormulaS-XXXIII. 4-bromo-6-chloropyridazin-3-amine can be converted to thecorresponding 4-aryl-6-chloropyridazin-3-amine (S-XXXII) using, forexample, an ArB(OH)₂ (e.g. phenylboronic acid) and a palladium catalyst(e.g. PdCl₂(PPh₃)₂) in typical Suzuki-Miyaura conditions. Subsequenttransformation of the amino group to a Cl via typical Sandmeyer reactionconditions (e.g. CuCl₂, t-Bu—ONO, acetonitrile, heat) affords compoundsof type S-XXXIII.

Scheme 10 describes the general synthesis of compounds of FormulaS-XXXVI. Compounds of formula S-XXXIV may be coupled with the phenolHO-CE-HD under a Cu(I) mediated coupling reaction in DMSO with base(e.g. K₂CO₃) at elevated temperature to afford intermediates of typeS-XXXV. Subsequent hydrolysis of the chloropyridazine via acetic acidand an acetate salt (e.g. NaOAc) affords products of formula S-XXXVIwhere the desired regioisomer can be isolated. In the context of scheme10, the group HD may contain a general protecting group that can becleaved at the stage of the intermediates S-XXXV or at the end of thesynthesis to afford compounds of formula S-XXXVI.

The synthesis of compounds of formula S-XXXVII can be performed usingliterature procedures. For example, an alkynylester can be combined witha protected aniline using a Ru catalyst under the conditions describedin Org. Lett. 2014, 16, 3568-3571 to afford 6-bromoquinolones.Alternatively, the compounds of formula S-XXXVII can be formed by otherprocedures reported in the literature, including but not limited to thefollowing examples: (a) Kadnikov, D. V.; et al. J. Org. Chem. 2004, 69,6772. (b) Manley, P. J.; et al. Org. Lett. 2004, 6, 2433. (c) Jia, C.;Piao, D.; et al. J. Org. Chem. 2000, 65, 7516. (d) Inamoto, K.; et al.J. Org. Chem. 2010, 75, 3900. (e) Ferguson, J.; et al. Org. Lett. 2013,15, 1998. (f) Fan, H; Org. Lett. 2018, 20, 7929-7932.

Alternatively, Scheme 11 depicts the synthesis of compounds of formulaS-XXXVII that can be made starting from a dihalogenated aminoaryl(S-XXXVII-a). The amine is then protected (e.g. trimethylacetamide) toafford an amide intermediate (S-XXXVII-b). Under strongly basicconditions (e.g. n-buLi, TIF) S-XXXVII-b reacts with an aldehydecontaining the desired Rg substitution to afford the alcohol productS-XXXVI-c, which is oxidized (via a common oxidizing agent; e.g.Dess-Martin reagent) in a subsequent step to afford the ketoneS-XXXVII-d. The ketone undergoes an aldol type reaction with a protectedester (e.g. t-butyl) to afford intermediate S-XXXVII-e. In the finalstep, an intramolecular cyclization can occur to afford the compounds offormula S-XXXVII.

Incorporation of the compounds of formula S-XXXVII to form finalproducts can occur using analogous methods as described in Schemes 6aand 6b.

Several methods exist to access compounds of formula XXXVIII and theyinclude but are not limited to the methods found in the followingreferences or referenced therein: (a) Hajra, S; et al. Org. Lett. 2018,20, 4540-4544. (b) Zaytsev, S. et al. Journal of Organic Chemistry(2018), 83(15), 8695-8709. (c) Wu, C; et al. Organic Letters (2014),16(7), 1960-1963. (d) Ye, N; et al. ACS Infect Dis. 2016, 2(6), 382-392.Incorporation of the compounds of formula S—XXXVIII to form finalproducts can occur using analogous methods as described in Schemes 6aand 6b.

As described in Scheme 12, a compound of Formula S-XXXIX is obtained bycoupling a compound of Formula S-VII with an azauracil compound ofFormula Int-A. The benzyloxymethyl acetal can then be deprotected usinga variety of methods described in the literature.

Pharmaceutical Compositions

In another aspect, disclosed herein are pharmaceutical compositionscomprising, consisting essentially of, or consisting of a compound asdescribed herein, and at least one pharmaceutically acceptableexcipient.

In another aspect, disclosed herein are pharmaceutical compositionscomprising a compound of Formula I, as described herein, and apharmaceutically acceptable diluent, excipient, or carrier. In someembodiments, disclosed herein are pharmaceutical compositionscomprising, consisting essentially of, or consisting of a compound ofFormula I, as described herein, and at least one pharmaceuticallyacceptable diluent, excipient, or carrier.

In another aspect, disclosed herein are pharmaceutical compositionscomprising, consisting essentially of, or consisting of a compound ofFormula I′, as described herein, and at least one pharmaceuticallyacceptable excipient.

The pharmaceutical composition disclosed herein may comprise apharmaceutically acceptable carrier, such as diluents, disintegrants,sweetening agents, glidants, or flavoring agents and may be formulatedinto an oral dosage form such as tablets, capsules, powders, granules,suspensions, emulsions, or syrups; or a parenteral dosage form such asliquids for external use, suspensions for external use, emulsions forexternal use, gels (ointments or the like), inhaling agents, sprayingagents, injections, etc. Said dosage forms may be formulated in variousforms, e.g., a dosage form for single administration or for multipleadministrations.

The pharmaceutical composition disclosed herein may include excipientssuch as lactose, corn starch, or the like, glidants such as magnesiumstearate, etc., emulsifying agents, suspending agents, stabilizers, andisotonic agents, etc. If desired, a sweetening agent and/or a flavoringagent may be added. Exemplary excipients include, without limitation,polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophors,carbohydrates, starches (e.g., corn starch), inorganic salts,antimicrobial agents, antioxidants, binders/fillers, surfactants,lubricants (e.g., calcium or magnesium stearate), glidants such as talc,disintegrants, diluents, buffers, acids, bases, film coats, combinationsthereof, and the like.

Specific carbohydrate excipients include, for example: monosaccharides,such as fructose, maltose, galactose, glucose, D-mannose, sorbose, andthe like; disaccharides, such as lactose, sucrose, trehalose,cellobiose, and the like; polysaccharides, such as raffinose,melezitose, maltodextrins, dextrans, starches, and the like; andalditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

Inorganic salt or buffers include, but are not limited to, citric acid,sodium chloride, potassium chloride, sodium sulfate, potassium nitrate,sodium phosphate monobasic, sodium phosphate dibasic, and combinationsthereof.

Suitable antioxidants for use in the present disclosure include, forexample, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite,and combinations thereof.

Additional exemplary excipients include surfactants such aspolysorbates, e.g., “Tween 20” and “Tween 80,” and pluronics such as F68and F88 (both of which are available from BASF, Mount Olive, N.J.),sorbitan esters, lipids (e.g., phospholipids such as lecithin and otherphosphatidylcholines, and phosphatidylethanolamines), fatty acids andfatty esters, steroids such as cholesterol, and chelating agents, suchas EDTA, zinc and other such suitable cations.

Further, a composition disclosed herein may optionally include one ormore acids or bases. Non-limiting examples of acids that can be usedinclude those acids selected from the group consisting of hydrochloricacid, acetic acid, phosphoric acid, citric acid, malic acid, lacticacid, formic acid, trichloroacetic acid, nitric acid, perchloric acid,phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Non-limiting examples of suitable bases include bases selected from thegroup consisting of sodium hydroxide, sodium acetate, ammoniumhydroxide, potassium hydroxide, ammonium acetate, potassium acetate,sodium phosphate, potassium phosphate, sodium citrate, sodium formate,sodium sulfate, potassium sulfate, potassium fumerate, and combinationsthereof.

The amount of any individual excipient in the composition will varydepending on the role of the excipient, the dosage requirements of theactive agent components, and particular needs of the composition.Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, preferably from about 5%to about 98% by weight, more preferably from about 15 to about 95% byweight of the excipient. In general, the amount of excipient present ina composition of the disclosure is selected from the following: at leastabout 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orsuitable carriers or excipient(s). Techniques for formulation andadministration of the compounds of the instant application may be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., 18th edition, 1990.

Suitable routes of administration may, for example, include oral,transdermal, rectal, transmucosal, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as inhalation, intrathecal, directintraventricular, intraperitoneal, intranasal, or intraocularinjections.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. These pharmaceuticalcompositions, then, may be formulated in a conventional manner using oneor more known physiologically acceptable carriers comprising excipientsand/or auxiliaries, which facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Any of thewell-known techniques, carriers, and excipients may be used as suitableand as understood in the art; e.g., in Remington's PharmaceuticalSciences, above.

Pharmaceutical compositions suitable for use in the presently disclosedformulations include compositions where the active ingredients arecontained in an amount effective to achieve its intended purpose. Morespecifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated. In someembodiments, a therapeutically effective amount means an amount ofcompound effective to alleviate or ameliorate symptoms of disease orprolong the survival of the subject being treated.

Although the exact dosage can be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.001 mg and 1000 mg of each ingredient, preferablybetween 0.01 mg and 500 mg, for example 1 to 200 mg or each activeingredient of the pharmaceutical compositions disclosed herein or apharmaceutically acceptable salt thereof calculated as the free base orfree acid, the composition being administered 1 to 4 times per day orper week. Alternatively, the compositions disclosed herein may beadministered by continuous such as sustained, delayed, or extendedrelease, preferably at a dose of each ingredient up to 500 mg per day.Thus, the total daily dosage by oral administration of each ingredientwill typically be in the range 0.1 mg to 2000 mg.

Methods of Treatment

In another aspect, disclosed herein are methods of treating a thyroidhormone receptor related disorder in a patient, the method comprising,consisting essentially of, or consisting of the steps of identifying apatient in need of treatment for the thyroid hormone receptor relateddisorder, and administering to the patient, or contacting the patientwith, a compound as described herein.

In another aspect, disclosed herein are methods of treating a thyroidhormone receptor related disorder in a patient, the method comprisingthe steps of identifying a patient in need of treatment for the thyroidhormone receptor related disorder, and administering to the patient, orcontacting the patient with, a compound of Formula I, as describedherein. In some embodiments, the method of treating a thyroid hormonereceptor related disorder in a patient consists essentially of orconsists of the steps of identifying a patient in need of treatment forthe thyroid hormone receptor related disorder, and administering to thepatient, or contacting the patient with, a compound of Formula I, asdescribed herein.

In another aspect, disclosed herein are methods of treating a thyroidhormone receptor related disorder in a patient, the method comprising,consisting essentially of, or consisting of the steps of identifying apatient in need of treatment for the thyroid hormone receptor relateddisorder, and administering to the patient, or contacting the patientwith, a compound of Formula I′, as described herein.

In some embodiments, a health care professional, such as a physician,physician's assistant, nurse practitioner, or the like, identifies anindividual as being in need of treatment for the thyroid hormonereceptor related disorder, and/or a candidate for treatment with acompound disclosed herein. The identification may be based on medicaltest results, non-responsiveness to other, first-line therapies, thespecific nature of the particular liver disorder, or the like.

In some embodiments, the thyroid hormone receptor related disorder isselected from non-alcoholic steatohepatitis (NASH), obesity,hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis,atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroidcancer.

In another aspect, disclosed herein are methods of treating a disorderor disease in a subject in need thereof, the method comprising,consisting essentially of, or consisting of administering to the subjecta therapeutically effective amount of a compound or compositiondisclosed herein, wherein the disorder or disease is selected fromnon-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia,hypercholesterolemia, diabetes, liver steatosis, atherosclerosis,cardiovascular diseases, hypothyroidism, and thyroid cancer.

In another aspect, disclosed herein are methods of treating NASH in asubject in need thereof, the method comprising, consisting essentiallyof, or consisting of administering to the subject a therapeuticallyeffective amount of a compound or composition disclosed herein.

In another aspect, disclosed herein are methods of treating obesity in asubject in need thereof, the method comprising, consisting essentiallyof, or consisting of administering to the subject a therapeuticallyeffective amount of a compound or composition disclosed herein.

In another aspect, disclosed herein are methods of treatinghyperlipidemia in a subject in need thereof, the method comprising,consisting essentially of, or consisting of administering to the subjecta therapeutically effective amount of a compound or compositiondisclosed herein.

In another aspect, disclosed herein are methods of treatinghypercholesterolemia in a subject in need thereof, the methodcomprising, consisting essentially of, or consisting of administering tothe subject a therapeutically effective amount of a compound orcomposition disclosed herein.

In another aspect, disclosed herein are methods of treating diabetes ina subject in need thereof, the method comprising, consisting essentiallyof, or consisting of administering to the subject a therapeuticallyeffective amount of a compound or composition disclosed herein.

In another aspect, disclosed herein are methods of treating liversteatosis in a subject in need thereof, the method comprising,consisting essentially of, or consisting of administering to the subjecta therapeutically effective amount of a compound or compositiondisclosed herein.

In another aspect, disclosed herein are methods of selectivelymodulating the activity of a thyroid hormone receptor beta (THR-β)comprising, consisting essentially of, or consisting of contacting acompound as described herein, with a thyroid hormone receptor. In someembodiments, the contacting is in vitro or ex vivo, whereas in otherembodiments, the contacting is in vivo.

In another aspect, disclosed herein are methods of selectivelymodulating the activity of a thyroid hormone receptor beta (THR-β)comprising contacting a compound of Formula I, as described herein, witha thyroid hormone receptor. In some embodiments, the contacting is invitro or ex vivo, whereas in other embodiments, the contacting is invivo. In some embodiments, the method of selectively modulating theactivity of a thyroid hormone receptor beta (THR-β) consists essentiallyof or consists of contacting a compound of Formula I, as describedherein, with a thyroid hormone receptor.

In another aspect, disclosed herein are methods of selectivelymodulating the activity of a thyroid hormone receptor beta (THR-β)comprising, consisting essentially of, or consisting of contacting acompound of Formula I′, as described herein, with a thyroid hormonereceptor. In some embodiments, the contacting is in vitro or ex vivo,whereas in other embodiments, the contacting is in vivo.

In another aspect, disclosed herein are methods of selectivelymodulating the activity of a thyroid hormone receptor beta (THR-β)comprising, consisting essentially of, or consisting of contacting acomposition described herein, with a thyroid hormone receptor. In someembodiments, the contacting is in vitro or ex vivo, whereas in otherembodiments, the contacting is in vivo.

EXAMPLES

The following exemplify aspects of the present invention and is notlimiting of its scope. Conditions for the preparation of several of thecompounds disclosed herein are presented. Procedures for the synthesisof common intermediates are provided only once. The chemical names weregenerated using Marvin 17.28.0 or Chemdraw 18.1.

The following abbreviations are used in the present disclosure:

Table of Abbreviations: Ac Acetate ACN Acetonitrile anhyd. Anhydrous aq.Aqueous Bu Butyl CAN Ceric ammonium nitrate conc. Concentrated DCMDichloromethane DIPEA N,N-Diisopropylethylamine DMAN,N-dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxideDPPA Diphenylphosphoryl azide dppf 1,1′-Bis(diphenylphosphino)ferroceneEA = EtOAc Ethyl acetate ECF Ethyl chloroformate Et Ethyl EtOH EthanolFA Formic acid g Gram(s) h Hour(s) Me Methyl MeOH Methanol min Minute(s)NIS N-Iodosuccinimide PE Petroleum ether rt Room temperature sat.Saturated Selectfluor ™ 1-Chloromethy1-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) TBAFTetra-n-butylammonium fluoride TBSCL t-Butyldimethylsilyl chloride TFATrifluoroacetic acid THF Tetrahydrofuran

Synthesis of Building Blocks 1. Synthesis of 3-isopropyl-1H-indol-5-ol

To a stirred mixture of (4-methoxyphenyl)hydrazine (10.00 g, 72.375mmol, 1.0 eq) in 100 mL of AcOH was added isovaleraldehyde (6.23 g,0.072 mmol, 1 eq) dropwise at 80° C. The resulting mixture was stirredfor 2 h at 120° C. The resulting mixture was concentrated under vacuum.The resulting mixture was extracted with EA (3×100 mL). The combinedorganic layers were washed with brine (1×100 mL), dried over anhydr.Na₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford 3-isopropyl-5-methoxy-1H-indole (2.6 g, 19%) as a brown solid.

To a solution of 3-isopropyl-5-methoxy-1H-indole (9.03 g, 47.713 mmol,1.0 eq) in DCM (100.00 mL) was added boron tribromide (35.88 g, 143.217mmol, 3 eq) dropwise for 1 h at −78° C. The resulting mixture wasstirred for additional 3 h at rt. The reaction was quenched by theaddition of H₂O at 0° C. The resulting mixture was extracted with EA.The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford 3-isopropyl-1H-indol-5-ol (5.86 g, 56%) as a black oil.

2a. Synthesis of 5-bromo-3-isopropyl-1H-indole

To a stirred solution of 4-bromophenyl-hydrazine (50.00 g, 267.32 mmol,1.00 eq) in AcOH (500 mL) was added isovaleraldehyde (23.03 g, 267.37mmol, 1.00 eq) dropwise at 80° C. The resulting mixture was stirred for3 h at 120° C. The resulting mixture was concentrated under vacuum. Theresulting mixture was extracted with EA (3×500 mL). The combined organiclayers were washed with brine (1×300 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography to afford5-bromo-3-isopropyl-1H-indole (28 g, 44%) as a brown solid.

2b. Synthesis of5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine

To a stirred solution of 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine(2.0 g, 8.36 mmol, 1 eq), DMAP (20.44 mg, 167.29 μmol, 0.02 eq) andDIPEA (2.38 g, 18.40 mmol, 2.2 eq) in DCM (60 mL) was added TosCl (1.91g, 10.04 mmol, 1.2 eq) at 20° C. Then the resulting mixture was stirredat 20° C. for 12 h. TLC (Petroleum ether/Ethyl acetate=5/1, UV) showedthe starting material was consumed completely. The mixture was dilutedwith H₂O (100 mL) and extracted with DCM (100 mL×3). The combinedorganic layers were washed with brine (200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash silica gel chromatography (Ethyl acetate in Petroleumether=0˜10%) to give5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (2.6 g,5.61 mmol, 67.0% yield) as an off-white solid.

2c. Synthesis of 5-bromo-3-pentyl-1H-indazole

To a solution of 5-bromo-2-fluoro-benzaldehyde (25 g, 123.15 mmol, 1 eq)in THF (100 mL) was added bromo(pentyl)magnesium (1 M, 184.73 mL, 1.5eq) at 0° C. The mixture was stirred at 20° C. for 1 hr. The reactionmixture was quenched by addition sat. aq. NH₄C₁ (50 mL) at 0° C., andthen diluted with H₂O (50 mL) and extracted with EA (100 mL*2). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by flash silica gel chromatography(Eluent of 0-30% Ethyl acetate/Petroleum ether) to give1-(5-bromo-2-fluoro-phenyl)hexan-1-ol (9.5 g, 34.53 mmol, 28% yield) ascolorless oil.

To a solution of 1-(5-bromo-2-fluoro-phenyl)hexan-1-ol (9.5 g, 34.53mmol, 1 eq) in DCM (100 mL) was added 4A MS (10 g) and PDC (25.98 g,69.05 mmol, 2 eq) at 20° C. The mixture was stirred at 20° C. for 12 h.The mixture was filtered and concentrated under reduced pressure to givea residue, which was purified by flash silica gel chromatography (Eluentof 0˜30% Ethyl acetate/Petroleum ether) to give1-(5-bromo-2-fluoro-phenyl)hexan-1-one (8.2 g, 30.02 mmol, 87% yield) asa pale yellow solid.

To a solution of 1-(5-bromo-2-fluoro-phenyl)hexan-1-one (5 g, 18.31mmol, 1 eq) in NMP (2 mL) was added hydrazine hydrate (2.16 g, 36.61mmol, 2.09 mL, 85% purity, 2 eq) at 20° C. The mixture was stirred at100° C. for 12 h. The reaction mixture was added to ice water (50 mL)and extracted with EA (50 mL*2). The combined organic layers were washedwith brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by flash silica gel chromatography (Eluent of 0˜20% Ethylacetate/Petroleum ether) to give 5-bromo-3-pentyl-1H-indazole (2 g, 7.49mmol, 41% yield) as a white solid.

3. Synthesis of3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde

To a stirred solution of 5-bromo-3-isopropyl-1H-indole (3.0 g, 12.6mmol, 1.00 eq) in toluene (50 mL) was added Bu₄NHSO₄ (0.43 g, 1.27 mmol,0.10 eq) in portions at 0° C. TsC1 (2.90 g, 15.26 mmol, 1.2 eq) wasadded dropwise at 0° C. The resulting mixture was stirred overnight atrt. The resulting mixture was concentrated under vacuum. The resultingmixture was extracted with EA (3×100 mL). The combined organic layerswere washed with brine (1×200 mL), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford5-bromo-3-isopropyl-1-(4-methylbenzenesulfonyl)indole (4.0 g, 67%) as alight yellow solid.

To a stirred solution of5-bromo-3-isopropyl-1-(4-methylbenzene-sulfonyl)indole (4 g, 10.2 mmol,1.00 eq) in THF were added n-BuLi (31.2 ml, 51.0 mmol, 5.0 eq, 1.6 M inhexane) dropwise at −78° C. under nitrogen atmosphere. The resultingmixture was stirred for 40 min at −78° C. under nitrogen atmosphere. DMF(3.70 g, 0.051 mmol, 5.0 eq) was added at −78° C. under nitrogenatmosphere. The resulting mixture was stirred for 1.5 h at −78° C. undernitrogen atmosphere. The reaction was quenched with water (50 mL). Theresulting mixture was extracted with EA (3×100 mL). The combined organiclayers were washed with brine (1×200 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography to afford3-isopropyl-1-(4-methylbenzenesulfonyl)indole-5-carbaldehyde (1.1 g,31%) as a light yellow oil.

4. Synthesis of4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione

6-bromo-2,4-dihydro-1,2,4-triazine-3,5-dione (10.00 g, 52.091 mmol, 1.00eq) was placed in acetic anhydride (50 mL) under reflux (140° C.) for 5h. After dry concentration of the reaction medium, a precipitate isisolated and then recrystallized from ether to get the desired product.The desired product was isolated as a light yellow solid (11.6 g, 95%pure, 90% yield). NaH (2.19 g, 54.755 mmol, 1.10 eq, 60%) was placed inDMF (50 mL) under nitrogen. A solution of2-acetyl-6-bromo-4H-1,2,4-triazine-3,5-dione (11.60 g, 49.571 mmol, 1.0eq) in DMF (150 mL) was poured dropwise. The reaction medium was stirredfor 1 h at rt and then [(chloromethoxy)methyl]benzene (8.54 g, 54.53mmol, 1.1 eq) was added and stirred then continues for 18 h at rt. Afterdry concentration the obtained residue was taken up with H₂O (200 mL)and extracted with ethyl acetate (EA) (3×500 mL). After drying onNa₂SO₄, the organic phase are evaporated and the obtained clear oil waspurified and 15 g of crystals were isolated. Crystals were placed inEtOH (400 mL) in the presence of TsOH (100.0 mg, 0.581 mmol, 0.01 eq).This mixture was heated with reflux for 4 h and then dry concentrated.The residue was taken up with H₂O and then extracted with EA. Afterdrying and evaporation of the organic phases, the desired product wasobtained as a yellow oil (9.5 g, yellow oil, 90% pure, 61% yield).

5a. Synthesis of 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione

To a stirred solution of 6-bromo-2,4-dihydro-1,2,4-triazine-3,5-dione(200.0 mg, 1.04 mmol, 1.0 eq) in ACN (5 mL) were added BSA (529.8 mg,2.61 mmol, 2.5 eq) dropwise at 0° C. under argon atmosphere. Theresulting mixture was stirred for 3 h at 82° C. under argon atmosphere,and then added CH₃I (251.4 mg, 1.77 mmol, 1.7 eq) dropwise at 82° C.,continued stirred 20 h at 82° C. The mixture was allowed to cool down tort, concentrated under reduced pressure, and then dissolved in DCM,washed with water and brine, dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to afford6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (870 mg, 69%) as a yellowsolid.

5b. Synthesis of 6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione

6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione was prepared similarly asdescribed for 6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione using 2.5 eqof iodoethane instead of 1.7 eq CH₃I.

6. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole

To a stirred solution of 3-isopropyl-1H-indol-5-ol (1.00 g, 5.71 mmol,1.00 eq) in THF was added tert-butoxypotassium (0.64 g, 5.70 mmol, 1.0eq) dropwise at 0° C. The resulting mixture was stirred for 30 min atrt. After completion of reaction, the resulting mixture was concentratedunder vacuum and re-dissolved by DMF. The second reaction flask: To astirred solution of 1,2,3-trichloro-5-nitrobenzene (1.29 g, 5.70 mmol,1.0 eq) in DMF was added the first reaction flask at 0° C. The resultingmixture was stirred for 5 min at 0° C., and then warmed to 100° C. andstirred for 1 h. The resulting mixture was extracted with EA. Thecombined organic layers were washed with brine and dried over anhydrousNa₂SO₄. The residue was purified by silica gel column chromatography toafford 5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.3 g,55%) as a yellow solid.

7. Synthesis of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole

To a stirred mixture of 3-isopropyl-1H-indol-5-ol (5.10 g, 29.10 mmol,1.0 eq) in 50 mL of DMSO were added K₂CO₃ (4.42 g, 32.0 mmol, 1.1 eq)and 2-fluoro-1,3-dimethyl-5-nitrobenzene (4.92 g, 29.1 mmol, 1.0 eq) inportions at rt. The resulting mixture was stirred for 2 h at 100° C. Theresulting mixture was extracted with EA (3×100 mL). The combined organiclayers were washed with brine (3×50 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography to afford5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (6 g, 64%) as alight yellow solid.

8. Synthesis of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole

To a solution of 5-hydroxyindol (16.0 g, 120.2 mmol, 1.0 eq) inacetonitrile (320 mL) was added potassium tert-butoxide (13.48 g, 120.2mmol, 1.0 eq) at 0° C. After 20 mins, the mixture was concentrated toremove acetonitrile and dissolved in N,N-dimethylformamide (320 mL).Then 1,2,3-trichloro-5-nitrobenzene (27.21 g, 120.2 mmol, 1.00 eq) wasadded at 0° C. The resulting solution was stirred at 100° C. overnightand then quenched with water (300 mL). The resulting solution wasextracted with ethyl acetate (3×500 mL) and the organic layers werecombined, washed with brine (2×300 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified to provide 28 g (68% yield) of5-(2,6-dichloro-4-nitrophenoxy)-1H-indole as yellow solid.

9. Synthesis of5-dichloro-4-[[3-isopropyl-1-(4-methy-lbenzenesu-lfonyl)indol-5-yl]oxy]aniline

To a stirred solution of5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1H-indole (1.29 g, 3.532mmol, 1.0 eq) in toluene (50.00 mL) was added TsCl (0.81 g, 4.239 mmol,1.2 eq) in toluene (10 mL), KOH (50%) (21.4 mL), Bu₄NHSO₄ (0.12 g, 0.353mmol, 0.1 eq) dropwise at 0° C. The resulting mixture was stirred for 6h at rt. After completion of reaction, the resulting mixture wasextracted with EA (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography to afford5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole(1.40 g, 75%) as a yellow solid.

To a stirred solution of5-(2,6-dichloro-4-nitrophenoxy)-3-isopropyl-1-(4-methylben-zenesul-fonyl)indole(1.40 g, 2.73 mmol, 1.0 eq) and NH₄Cl (1.16 g, 21.62 mmol, 8.0 eq) inEtOH (50 mL) and H₂O (25 mL) was added Fe powder (0.75 g, 13.514 mmol,5.00 eq) in portions at rt under nitrogen atmosphere. The resultingmixture was stirred for 2 h at 50° C. under nitrogen atmosphere. Theresulting mixture was filtered, the filter cake was washed with EA. Thefiltrate was concentrated under reduced pressure. The aqueous layer wasextracted with EA, dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to afford3,5-dichloro-4-[[3-isopropyl-1-(4-methy-lbenzenesulfonyl)-indol-5-yl]oxy]aniline(1.11 g, 78%) as a white solid.

10. Synthesis of4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylaniline

To a stirred mixture of5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indole (5.00 g, 15.414mmol, 1.00 eq) in 50 mL of toluene were added TsCl (3.53 g, 0.018 mmol,1.2 eq), Bu₄NHSO₄ (0.52 g, 0.002 mmol, 0.1 eq), KOH (50 mL) dropwise at0° C. The mixture was stirred overnight at rt and quenched with water(50 mL). The resulting mixture was extracted with EA (3×200 mL). Thecombined organic layers were washed with brine (1×100 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography in hexane to afford5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzenesulfonyl)indole(5.8 g, 79%) as a light yellow solid.

To a stirred mixture of5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1-(4-methylbenzene-sulfonyl)indole(5.80 g, 12.120 mmol, 1.0 eq) in MeOH (70 mL) were added Pd/C (1.74 g)in portions. The resulting mixture was stirred overnight at rt underhydrogen atmosphere. The resulting mixture was filtered, the filter cakewas washed with MeOH (1×500 mL). The filtrate was concentrated underreduced pressure to get a residue, which was purified by silica gelcolumn chromatography to afford4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethyl-aniline(3.2 g, 59%) as a light yellow solid.

11. Synthesis of4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline

To a stirred solution ofN-(4-bromo-3,5-dimethylphenyl)-2,2,2-trifluoro-acetamide (260.16 mg,0.879 mmol, 1.0 eq) in THF (5 mL) under nitrogen was added MeLi—LiBr(1.7 mL, 1.76 mmol, 2.0 eq, 1 M in ether) at −78° C. Then t-BuLi (1.6mL, 2.64 mmol, 3.00 eq, 1.6M in hexane) was added dropwise at −78° C.The mixture was stirred for 20 min at −78° C.3-isopropyl-1-(4-methylbenzene-sulfonyl)indole-5-carbaldehyde (300 mg,0.879 mmol, 1.0 eq) was added at −78° C. The resulting mixture wasstirred for 1 h at rt. The reaction was quenched with water (10 mL) atrt. The resulting mixture was extracted with EA (3×50 mL). The combinedorganic layers were washed with brine (2×100 mL), dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified to afford2,2,2-trifluoro-N-(4-[hydroxy[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide(300 mg, 61%) as a white solid.

A solution of2,2,2-trifluoro-N-(4-[hydroxy[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide(300.0 mg, 0.537 mmol, 1.00 eq) in DCM (5 mL) was stirred under nitrogenat 0° C. Then a solution of Et₃SiH (374.7 mg, 3.22 mmol, 6.0 eq) in DCM(15 mL) and TMSOTf (7.16 mg, 0.032 mmol, 0.06 eq) in DCM (5 mL) wasadded dropwise to the reaction mixture. The reaction mixture was stirredfor 30 min at 0° C. and 1.5 h at rt. The reaction mixture was quenchedwith saturated NaHCO₃ solution (20 mL). The resulting solution wasextracted with dichloromethane (3×50 mL) and the organic layers werecombined, washed with brine (2×30 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude product. The crude product containing2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamidewas isolated as a yellow solid (260 mg, 85% pure, 76% yield).

To a solution of2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide(260.0 mg, 0.479 mmol, 1.0 eq) in MeOH (10 mL) and H₂O (2 mL) stirredunder nitrogen at rt was added NaOH (76.66 mg, 1.917 mmol, 4.0 eq). Thereaction mixture was stirred at 60° C. overnight. The reaction mixturewas quenched with water (20 mL). The resulting solution was extractedwith dichloromethane (3×50 mL) and the organic layers were combined,washed with brine (2×30 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford crudeproduct. The crude product was isolated as a yellow solid containing4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline(230 mg, 90% pure, 97% yield).

12. Synthesis of3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (28.0 g,86.65 mmol, 1.0 eq) in toluene (720 mL) was added tetrabutylammoniumhydrogen sulfate (2.94 g, 8.665 mmol, 0.10 eq) and potassium hydroxide(120.00 g, 2138.8 mmol, 25.0 eq) in water (120 mL) at 0° C. 4-Toluenesulfonyl chloride (19.82 g, 103.98 mmol, 1.20 eq) in toluene (720 mL)was added dropwise at 0° C. Then the reaction was stirred at rt for 3 hand quenched with water (200 mL). The mixture was extracted with ethylacetate (3×500 mL) and the organic layers were combined, concentratedunder reduced pressure. The residue was purified to provide5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole (34 g,78% yield) as yellow solid.

To a solution of5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzene-sulfonyl)-indole(26.00 g, 54.47 mmol, 1.0 eq) in ethanol (500 mL) and water (250 mL) wasadded iron dust (15.21 g, 272.36 mmol, 5.0 eq) and ammonium chloride(23.31 g, 435.78 mmol, 8.0 eq). The resulting solution was stirred for 2h at 50° C. The resulting mixture was filtered, the filter cake waswashed with dichloromethane (6×100 mL). The filtrate was extracted withdichloromethane (3×500 mL). The combined organic layers were combined,washed with brine (300 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to provide3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline (23g, 88% yield) of as a light yellow solid.

13a. Synthesis of6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one

To a solution of 3,6-dichloropyridazine (50.00 g, 335.64 mmol, 1.0 eq)in H₂O (1.20 L) was added AgNO₃ (57.02 g, 335.64 mmol, 1.0 eq),isobutyric acid (29.57 g, 335.64 mmol, 1.0 eq) in portions at rt underair atmosphere and then stirred at 50° C. under nitrogen atmosphere.H₂SO₄ (98.76 g, 1006.9 mmol, 3.0 eq) was added in portions at 50° C. andstirred at 60° C. Then (NH₄)₂S₂O₈ (229.78 g, 1006.914 mmol, 3.0 eq) wasadded and stirred for 30 min at 70° C. under nitrogen atmosphere. Themixture was neutralized to pH 9 with NaOH solution. The resultingmixture was extracted with EA (3×1 L). The combined organic layers werewashed with brine (2×1 L), dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography to afford3,6-dichloro-4-isopropylpyridazine (30 g, 47%) as a light yellow oil.

To a solution of 3,6-dichloro-4-isopropylpyridazine (20.00 g, 104.679mmol, 1.0 eq) in DMSO (200 mL) were added phenol, 4-amino-2,6-dichloro-(18.63 g, 104.68 mmol, 1.0 eq), K₂CO₃ (58.16 g, 420.81 mmol, 4.02 eq)and CuI (11.96 g, 62.81 mmol, 0.60 eq) in portions. The resultingmixture was stirred overnight at 90° C. under nitrogen atmosphere. Themixture was acidified to pH 8 with conc. HCl. The resulting mixture wasextracted with EA (3×500 mL). The combined organic layers were washedwith brine (3×300 mL), dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated. The residue was purified by silica gelcolumn chromatography to afford3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline (17 g,49%) as a green solid.

To a solution of3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (17.00g, 51.111 mmol, 1.0 eq) in HOAc (200 mL) was added NaOAc (24.33 g,178.89 mmol, 3.50 eq) in portions. The mixture was stirred overnight at100° C. under nitrogen atmosphere. The mixture was added NaOH (12.27 g,306.77 mmol, 6.0 eq), and MeOH (200 mL) in portions. The resultingmixture was stirred overnight at 120° C. under nitrogen atmosphere. Theresulting mixture was extracted with EA (3×500 mL). The combined organiclayers were washed with brine (2×200 mL), dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated. The residue waspurified by silica gel column chromatography to afford6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (11 g,69%) as a off-white solid.

13b. Synthesis of3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline

A mixture of 3,6-dichloro-4-isopropylpyridazine (80.0 g, 419 mmol, 1.00eq), 4-amino-2,6-dichlorophenol (74.5 g, 419 mmol, 1.0 eq), K₂CO₃ (232g, 1675 mmol, 4.0 eq) and CuI (47.9 g, 251 mmol, 0.6 eq) in DMSO (800mL) was stirred overnight at 60° C. After cooled down to 25° C., thesolution was then poured onto ice water (3 L) and the pH of the mixturewas adjusted to 8 with hydrochloric acid (3 N). The resulting mixturewas extracted with EA (3×1 L). The combined organic layers were washedwith brine (3×1 L), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluting with petroleumether to ethyl acetate ratio (PE:EA) of 5:1) to afford3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline (35.0 g,24% yield) as an off-white solid. LCMS (ESI, m z): 332 [M+H]⁺.

A mixture of3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-aniline (10.0g, 30.1 mmol, 1.00 eq) and potassium methoxide (21.1 g, 301 mmol, 10.0eq) in MeOH (50 mL) was stirred for 48 h at 65° C. After cooled down to25° C., the PH value of the mixture was adjusted to 6-7 withhydrochloric acid (1 N). The resulting mixture was extracted with EA(3×500 mL). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (eluting with PE:EA of5:1) to afford3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]aniline (6.80g, 65% yield) as a white solid.

LCMS (ESI, m z): 328 [M+H]⁺.

14a. Synthesis of3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronicAcid

A 1000 mL round-bottom flask was charged with6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (14.13 g,44.98 mmol, 1.0 eq) in MeOH (200 mL). HCl (4.10 mL, 112.439 mmol, 3 eq)was added dropwise at 0° C. H₂O (100 mL) was added at 0° C. The mixturewas stirred for 10 min, then NaNO₂ (3.72 g, 53.971 mmol, 1.20 eq) wasadded, and was stirred for an additional 30 min at 0° C.Tetrahydroxydiborane (40.32 g, 449.749 mmol, 10.0 eq) was added. Thereaction was stirred for 1 h at 60° C. The resulting solution wasquenched with water (50 mL). The resulting solution was extracted withdichloromethane (3×400 mL) and the organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. Purification resulted in3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronicacid (6.3 g, 37%) as a white solid.

14b. Synthesis of3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronicacid

To a stirred mixture of3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]aniline (5.80g, 17.7 mmol, 1.00 eq) and CuBr₂ (7.89 g, 35.3 mmol, 2.00 eq) in ACN (40mL) were added tert-butyl nitrite (4.24 mL, 35.4 mmol, 2.0 eq) dropwiseat 0° C. The resulting mixture was then warmed up to room temperatureand stirred for an additional 3 h. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluting with PE:EA of 10:1) to afford6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (3.50 g,48% yield) as a yellow solid.

LCMS (ESI, m z): 391[M+H]⁺.

A mixture of6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-3-methoxypyridazine (1.00 g,2.55 mmol, 1.00 eq), bis(pinacolato)diboron (972 mg, 3.83 mmol, 1.50eq), Pd(dppf)Cl₂ (187 mg, 0.256 mmol, 0.10 eq) and KOAc (750 mg, 7.64mmol, 3.00 eq) in 1,4-dioxane (10 mL) was stirred for 2 h at 90° C.After cooled down to 25° C., the solids were filtered out and the filtercake was washed with EA (3×20 mL). The filtrate was concentrated underreduced pressure. The residue was purified by reverse phasechromatography (Column: C18 silica gel; Mobile phase, A: water(containing 0.5% TFA) and B: ACN (20% to 95% over 20 min) to afford3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronicacid (610 mg, 64% yield) as a brown solid.

LCMS (ESI, m z): 359 [M+H]⁺.

15. Synthesis of2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile

To a solution of3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]aniline(15.00 g, 33.532 mmol, 1.0 eq) in water (700 mL), concentratedhydrochloric acid (336 mL) and acetic acid (942 mL) was added sodiumnitrite (4.86 g, 70.418 mmol, 2.1 eq) in water (50 mL) dropwise at 0° C.After the addition, the reaction was stirred at 0° C. for 45 min. Thenthe reaction mixture was poured into a solution of ethylN-(2-cyanoacetyl)carbamate (7.85 g, 50.30 mmol, 1.5 eq) in water (600mL) and pyridine (336 mL) at 0° C. quickly. The resulting mixture wasstirred at 0° C. for 30 min and filtered. The filter cake was washedwith water (100 mL) and petroleum ether (200 mL), dried under reducedpressure to provide ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate (18.4 g, 80% yield) as red solid.

To a solution of ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(18.40 g, 29.95 mmol, 1.0 eq) in N,N-dimethylacetamide (300 mL) wasadded potassium acetate (11.76 g, 119.782 mmol, 4.0 eq). The reactionwas stirred at 120° C. for 2 h and quenched with water (100 mL). Themixture was extracted with ethyl acetate (3×100 mL) and the organiclayers were combined, washed with brine (100 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified to provide2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(14 g, 80% yield) as brown solid.

To a stirred solution of2-(3,5-dichloro-4-[[1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(7.0 g, 12.32 mmol, 1.0 eq) and p-toluenesulfonic acid (0.210 g, 1.232mmol, 0.1 eq) in dichloromethane (300 mL) was added N-iodosuccinimide(4.16 g, 18.47 mmol, 1.5 eq) at 0° C. under nitrogen atmosphere. Thereaction mixture was stirred for 6 h at 0° C. and quenched with water(200 mL). The resulting mixture was extracted with dichloromethane(3×200 mL) and the combined organic layers were combined, washed withsaturated sodium thiosulfate solution (2×500 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified to provide2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(5.30 g, 43% yield) as a brown solid.

16. Synthesis of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile

To a solution of6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one (500 mg,1.591 mmol, 1.0 eq) in HOAc (43.8 mL, 764.03 mmol) and HCl (15.3 mL,503.55 mmol) were added NaNO₂ (230.59 mg, 3.34 mmol, 2.1 eq) in H₂O(33.4 mL) dropwise at 0° C. The resulting mixture was stirred for 30 minat 0° C. under nitrogen atmosphere. The above solution was quicklypoured into the second reaction flask which was placed ethylN-(2-cyanoacetyl)carbamate (372.75 mg, 2.387 mmol, 1.5 eq) and H₂O (40.9mL) in pyridine (20 mL) at 0° C. The resulting mixture was for 30 min at0° C. The precipitated solids were collected by filtration and washedwith PE and H₂O (3×300 mL). to afford ethylN—[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazin-1-ylidene)-carbonyl]-carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-hydrazineylidene)acetyl)-carbamate(name generated by Chemdraw) (640 mg, 84%) as an orange solid.

To a solution of ethylN—[(Z)-cyano(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]hydrazin-1-ylidene)carbonyl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(640.00 mg, 1.330 mmol, 1.00 eq) in DMA (13.36 mL) was added KOAc(261.01 mg, 2.660 mmol, 2.00 eq) in portions at rt. The mixture wasstirred for 3 h at 120° C. under nitrogen atmosphere. The reaction wasquenched with Water. The resulting mixture was extracted with EA (3×100mL). The combined organic layers were washed with brine (4×100 mL),dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated. This resulted in2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(590 mg, 102%) as a dark orange solid.

17. Synthesis of4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-1,2,4-triazine-3,5-dione

To a solution of3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronicacid (5.00 g, 11.663 mmol, 1.0 eq) in DCM (200 ml) stirred at rt wasadded 4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (4.37 g,13.995 mmol, 1.2 eq), Cu(OAc)₂ (4.24 g, 23.326 mmol, 2 eq) and pyridine(1.85 g, 23.326 mmol, 2 eq). The reaction mixture was stirred for 2 daysat rt under oxygen, and was then concentrated under reduced pressure toafford the crude product. Purification resulted in4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-1,2,4-triazine-3,5-dione(2.2 g, yield 28%) as an off-white solid.

18. Synthesis of(E)-N′-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide

A 8 mL vial was charged with 6-chloro-2-methyl-3-nitropyridine (20.00 g,115.895 mmol, 1.0 eq), phenol, 4-amino-2,6-dichloro- (24.76 g, 139.07mmol, 1.2 eq), K₂CO₃ (48.05 g, 347.69 mmol, 3.0 eq) and DMF (200 mL).The resulting mixture was stirred overnight at 60° C. The reactionmixture was quenched with water (400 mL). The resulting mixture wasextracted with EA (3×500 mL) and the organic layers were combined,washed with brine (2×400 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford crudeproduct. The crude product was purified by silica gel columnchromatography and eluted with EA:PE (0%˜40% over 30 min) to provide thedesired product3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]aniline (36.4 g, 91%)as a yellow solid.

LCMS (ESI, m z): 314 [M+H]⁺.

To a solution of3,5-dichloro-4-[(6-methyl-5-nitropyridin-2-yl)oxy]-aniline (36.40 g,115.88 mmol, 1.0 eq) and (dimethoxymethyl)dimethylamine (33.14 g, 278.1mmol, 2.4 eq) in dimethylformamide (400 mL) was added TEA (11.73 g,115.9 mmol, 1.0 eq). The resulting mixture was stirred for 4 h at 100°C. The mixture was cooled to 60° C. and concentrated under reducedpressure to remove half of DMF. The resulting solution was passed to thenext step without further treatment.

A solution of(E)-N′-(3,5-dichloro-4-((6-((E)-2-(dimethylamino)vinyl)-5-nitropyridin-2-yl)oxy)phenyl)-N,N-dimethylformimidamide(49.17 g, 115.89 mmol, 1.0 eq) in DMF (200 mL) and MeOH (400 mL) wasadded Pd/C (10.0 g, 93.967 mmol, 0.81 eq) and NaOAc (9.51 g, 115.89mmol, 1.0 eq) under hydrogen. The resulting mixture was stirredovernight at room temperature. The mixture was filtered through a celitepad and washed with MeOH (50 mL). The filtrate was concentrated underreduced pressure to afford crude product. The crude product was purifiedby silica gel column chromatography and eluted with EA:PE (0%˜70% over30 min) to provide the desired product(E)-N′-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylmethanimidamide(21.5 g, 45%) as a brown solid.

LCMS (ESI, m z): 349 [M+H]⁺.

A solution of(E)-N′-(3,5-dichloro-4-[1H-pyrrolo[3,2-b]pyridin-5-yloxy]phenyl)-N,N-dimethylmethanimidamide(5.00 g, 14.32 mmol, 1.0 eq) and I₂ (4.00 g, 15.75 mmol, 1.1 eq) indimethylformamide (50 mL) was added KOH (3.21 g, 57.27 mmol, 4.0 eq).The resulting mixture was stirred overnight at room temperature andquenched with water (80 mL). The resulting mixture was extracted with EA(3×100 mL) and the organic layers were combined, washed with brine (2×80mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to afford crude product. The crude product wastriturated with PE:EA of 5:1 to provide the desired product(E)-N′-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide(5.9 g, 78%) as a yellow solid.

LCMS (ESI, m z): 475 [M+H]⁺.

19. Synthesis of3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline

To a solution of(E)-N′-[3,5-dichloro-4-([3-iodo-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide(3.0 g, 6.31 mmol, 1.0 eq), K₃PO₄ (2.01 g, 9.471 mmol, 1.5 eq) and1,1′-Bis (di-t-butylphosphino)ferrocene palladium dichloride (0.410 g,0.631 mmol, 0.10 eq) in dioxane (75 mL) and H₂O (15 mL) was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.24 g,25.26 mmol, 4.0 eq) under nitrogen. The resulting mixture was stirredovernight at 60° C. and quenched with water (100 mL). The resultingmixture was extracted with EA (3×150 mL) and the organic layers werecombined, washed with brine (2×100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to affordcrude product. The crude product was purified by column and eluted withEA:PE (0% 50% over 30 min) to provide the desired product(E)-N′-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(430 mg, 14%) as a yellow solid.

LCMS (ESI, m z): 389 [M+H]⁺.

To a solution of(E)-N′-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(400.0 mg, 1.028 mmol, 1.0 eq) in MeOH (25 mL) was added Pd/C (250.0 mg,2.349 mmol, 2.3 eq). The resulting mixture was stirred for 1 h at roomtemperature under hydrogen atmosphere. The mixture was filtered througha celite pad and washed with MeOH (20 mL). The combined organic layerswere concentrated under reduced pressure to afford crude product(E)-N′-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]-oxy)phenyl]-N,N-dimethylmethanimidamide(380 mg, crude) as a yellow solid.

LCMS (ESI, m z): 391 [M+H]⁺.

To a solution of(E)-N′-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-N,N-dimethylmethanimidamide(380.0 mg, 0.97 mmol, 1.0 eq) in ethyl alcohol (25 mL) was addedethylenediamine (262.6 mg, 4.37 mmol, 4.5 eq). The resulting mixture wasstirred refluxed overnight. The reaction mixture was concentrated underreduced pressure to afford the crude product3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline(350 mg, crude) as a yellow-semi solid.

LCMS (ESI, m z): 336 [M+H]⁺.

20. Synthesis of4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione

A mixture of3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenylboronicacid (400 mg, 1.12 mmol, 1.0 eq),4-[(benzyloxy)methyl]-6-bromo-2H-1,2,4-triazine-3,5-dione (398 mg, 1.28mmol, 1.15 eq), PdAmphos(Cl)₂ (79.3 mg, 0.112 mmol, 0.1 eq) and K₃PO₄(713 mg, 3.36 mmol, 3.0 eq) in 1,4-dioxane (8 mL)/water (0.8 mL) wasstirred for 2 h at 90° C. After cooled down to 25° C., the solids werefiltered out and the filter cake was washed with EA (3×15 mL). Thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluting with PE:EA of 1:1)to afford4-[(benzyl-oxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]-phenyl]-2H-1,2,4-triazine-3,5-dione(190 mg, 30% yield) as a light yellow solid.

LCMS (ESI, m z): 544 [M+H]⁺.

21. Procedures for the synthesis of2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 5-benzyloxy-2-bromo-1,3-dimethyl-benzene (1 g, 3.43mmol) and4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)meth-yl]-1,3,2-dioxaborolane(1.84 g, 6.87 mmol) in dioxane (10 mL) was added 8 N aq. KOH (858.57 μL,6.86 mmol), followed by addition of Pd[P(t-Bu)_(3]2) (87.75 mg, 171.71μmol) at rt (˜15° C.) under N₂ protection. Then the mixture was stirredat 30° C. for 18 h. TLC (PE:EA of 10:1, stained by 12) showed thebromide was consumed completely and two new spots formed. The mixturewas diluted with water (40 mL), extracted with ethyl acetate (50×2 mL).The combined organic phases were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give crude product, which was purified byflash silica gel chromatography (Eluent of 0˜2% Ethyl acetate/Petroleumether) to give desired2-(4-(benzyloxy)-2,6-dimethylbenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane(870 mg, 72% yield) as a white solid.

22. Synthesis of[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate

To a solution of5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine (1.0 g,2.54 mmol, 1 eq) and2-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.79 g, 5.09 mmol, 2 eq) in dioxane (30 mL) and H₂O (6 mL) was addeddichloropalladium; tris-o-tolylphosphane (299.79 mg, 381.39 μmol, 0.15eq) and K₃PO₄ (1.62 g, 7.63 mmol, 3 eq) at 20° C. under N₂ protection.Then the resulting mixture was stirred at 100° C. for 15 h under N₂atmosphere. The combined mixture (combined with 300 mg batch) wasdiluted with H₂O (100 mL) and extracted with EA (100 mL×3). The combinedorganic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue, which was purified by flash silica gel chromatography (Ethylacetate in Petroleum ether=0˜10%) to give5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine(1.36 g, 2.44 mmol, 74% yield, 96.5% purity) as a yellow solid.

To a solution of5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine(1.36 g, 2.52 mmol, 1 eq) in MeOH (20 mL) and THF (10 mL) was addedPd—C(10%, 1.07 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (50 psi)at 35° C. for 18 hours. The mixture was filtered and the filtrate wasconcentrated, purified by flash silica gel chromatography (0˜100% Ethylacetate in Petroleum ether) to give4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol(1 g, 2.23 mmol, 88% yield) as a white solid.

To a solution of4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol(1 g, 2.23 mmol, 1 eq) and pyridine (440.84 mg, 5.57 mmol, 2.5 eq) inDCM (25 mL) at 0° C. was added dropwise Tf₂O (754.76 mg, 2.68 mmol,441.38 μL, 1.2 eq) slowly. After the addition, the mixture was stirredat 0° C. for 1 h. The reaction mixture was partitioned between H₂O (30mL) and DCM (30 mL). The organic phase was separated, washed with brine(10 mL*3), dried over anhydrous MgSO₄, filtered and concentrated to givecrude product, which was purified by flash silica gel chromatography(0˜10% Ethyl acetate in Petroleum ether) to give[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (1.25 g, 2.15 mmol, 97% yield) as a colorlessgum.

23. Synthesis of4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline

To a solution of[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (300 mg, 516.67 μmol, 1 eq) and tert-butylcarbamate (121.05 mg, 1.03 mmol, 2 eq) in dioxane (8 mL) was addedPd₂(dba)₃ (47.31 mg, 51.67 μmol, 0.1 eq),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(59.79 mg, 103.33 μmol, 0.2 eq) and Cs₂CO₃ (505.03 mg, 1.55 mmol, 3 eq)at 20° C. under N₂ protection. Then the resulting mixture was stirred at100° C. for 15 h under N₂. LCMS showed the reaction was complete. Themixture was diluted with H₂O (50 mL) and extracted with EA (50×3 mL).The combined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash silica gelchromatography (Ethyl acetate in Petroleum ether=0˜10%) to givetert-butylN-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]carbamate (200 mg, 350.19 μmol, 68% yield, 95.9% purity) as a lightyellow solid.

To a solution of tert-butylN-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]carbamate (170 mg, 310.39 μmol, 1 eq) in MeOH (3 mL) was added 4 M HClgas in MeOH (8 mL) at 20° C. Then the resulting mixture was stirred at20° C. for 12 h. MeOH was removed under reduced pressure and the residuewas partitioned between EA (50 mL) and H₂O (50 mL). The EA phase waswashed with H₂O (50 mL) again. The combined aqueous layers were adjustedto pH 7˜8 with sat. aq. NaHCO₃, then extracted with EA (50 mL×2). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to give4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline(120 mg, 261.40 μmol, 84% yield, 97.5% purity) as a light yellow solid.

24. Synthesis of2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide

Trifluoroacetic anhydride (2 eq, 5.63 mL) was added to a solution of4-iodo-3,5-dimethylaniline (1 eq, 5 g, 20.24 mmol) in anhydrous DCM (150mL) under N₂ at 0° C. Then, the reaction mixture was stirred at 25° C.for 2.5 hours. To the reaction mixture was added water (200 mL), thelayers were separated, and the aqueous layer was extracted with DCM(2×150 mL). The combined organic layers were dried over MgSO₄, filteredand evaporated to dryness. The crude mixture was purified by flashchromatography on silica gel (DCM) to give2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (6.35 g, 91%) asa white solid.

Anhydrous THF (35 mL) was added to a mixture of2,2,2-trifluoro-N-(4-iodo-3,5-dimethylphenyl)acetamide (1 eq, 2.40 g, 7mmol) and NaH 60% (1.5 eq, 420 mg) under N₂ at 0° C. The reactionmixture was stirred at 25° C. for 1.5 h, then cooled to −78° C. andt-BuLi (2.4 eq, 9.88 mL) was added dropwise. The reaction mixture wasstirred at −78° C. for 40 min. Then, anhydrous DMF (5 eq, 2.71 mL) wasadded and the reaction was further stirred at −78° C. for 1 h. Thereaction mixture was hydrolyzed with sat. aq. NH₄Cl (5 mL), poured inDCM (250 mL) and washed 4 times with brine. The combined organic layerswere dried over MgSO₄, filtered and evaporated to dryness. The crudemixture was recrystallized from hot EtOH to give2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (317 mg, 19%)as a yellow solid. The supernatant was recrystallized from hot tolueneto give more 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide(909 mg, 53%) as a light yellow solid.

25. Synthesis of3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline

Anhydrous THF (8.3 mL) was added to a mixture of5-bromo-3-pentyl-1H-indazole (1 eq, 668 mg, 2.5 mmol) and NaH 60% (1.5eq, 150 mg) at 0° C., under N₂. The resulting reaction mixture wasstirred at 25° C. for 1 h. Then, the mixture was cooled to −78° C. andn-BuLi (1.5 eq, 2.34 mL) was added dropwise and the reaction mixture wasstirred at −78° C. for 2 h. Then, a solution of2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (1 eq, 613 mg)in anhydrous THF (8.3 mL) was added dropwise to the reaction mixture at−78° C. The reaction was further stirred at this temperature for 1.75 hand finally hydrolyzed with sat. aq. NH₄C₁ (5 mL), poured in DCM (100mL) and washed 3 times with water. The organic phase was dried overMgSO₄, filtered and evaporated to dryness. The crude mixture waspurified by flash chromatography on silica gel (20% to 40% EA inCyclohexane) to give2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide(317 mg, 29%) as a white solid.

A solution of Et₃SiH (6 eq, 0.71 mL) in anhydrous DCM (20 mL) followedby a solution of TMSOTf (0.075 eq, 0.01 mL) in anhydrous DCM (7 mL) wereadded dropwise to a solution of2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide(1 eq, 317 mg, 0.73 mmol) in anhydrous DCM (7 mL) at 0° C. under N₂. Thereaction was stirred at 0° C. for 1 h, at which point the ice bath wasremoved and the reaction was stirred at 25° C. After 19 h, extra Et₃SiH(6 eq, 0.71 mL) and TMSOTf (0.075 eq, 0.01 mL) were added and thereaction mixture was further stirred at 25° C. for 5 h. Then, thereaction was quenched with sat. aq. NaHCO₃ (20 mL) and the aqueous phasewas extracted 3 times with DCM (3×50 mL). The combined organic layerswere washed with brine (150 mL), dried over MgSO₄, filtered andevaporated to dryness. The crude mixture was purified by flashchromatography on silica gel (0% to 30% EA in Cyclohexane) to giveN-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide(144 mg, 47%) as a white solid.

NaOH (4 eq, 54 mg) was added to a solution ofN-(3,5-di-methyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)-2,2,2-trifluoroacetamide(1 eq, 141 mg, 0.34 mmol) in MeOH (7 mL) and water (1.4 mL) under N₂.The reaction mixture was stirred at 60° C. for 90 h. Then, the reactionmixture was quenched with water (30 mL). The resulting solution wasextracted with DCM (3×20 mL) and the combined organic layers were washedwith brine (2×20 mL), dried over MgSO₄, filtered and evaporated todryness to give 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline(105 mg, 97%) as a white solid, which was used without furtherpurification.

Example 1: Synthesis of Compound 1

To a stirred solution of3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]aniline(1.11 g, 2.277 mmol, 1.00 eq) in HCl (21.90 mL), HOAc (62.50 mL) and H₂O(47.68 mL) was added NaNO₂ (0.32 g, 4.566 mmol, 2 eq) in H₂O (4.2 mL)dropwise for 1 h at 0° C. The second reaction flask was placed ethylN-(2-cyanoacetyl)carbamate (0.53 g, 3.424 mmol, 1.5 eq) in H₂O (58.41mL) and Pyridine (22.35 mL) for 10 min at 0° C. The above solution wasquickly poured into the second reaction flask for 30 min at 0° C. Theprecipitated solids were collected by filtration and washed with waterand PE. The resulting mixture was concentrated under vacuum. Thisresulted in ethylN—[(Z)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]phenyl)-hydrazin-1-ylidene]carbonyl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamateas a red solid.

To a stirred solution of ethylN—[(Z)-cyano[2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]-oxy]phenyl)hydrazin-1-ylidene]-carbonyl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(1.16 g, 1.773 mmol, 1.00 eq) in DMA (20.00 mL) was added KOAc (0.35 g,3.546 mmol, 2 eq) in portions at rt. The resulting mixture was stirredfor 2 h at 120° C. under nitrogen atmosphere. The reaction was quenchedby the addition of water (10 mL) at rt. The precipitated solids werecollected by filtration and washed with water (3×10 mL). The solid wasdried overnight at rt to afford2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(521.2 mg, 45%) as a red solid.

To a stirred solution of2-(3,5-dichloro-4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(521.20 mg, 0.854 mmol, 1.00 eq) in THF (20.00 mL) was added TBAF (20mL) in portions at rt under nitrogen atmosphere. The resulting mixturewas stirred for 20 h at 65° C. under nitrogen atmosphere. The reactionwas quenched with H₂O. The resulting mixture was extracted with EA,washed with brine, dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by Prep-TLC (DCM:MeOH 16:1) to afford the crude product (200mg). The crude product (200 mg) was purified by prep-HPLC to afford2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrile(11.5 mg, 3%, compound 1) as a yellow solid.

¹H-NMR: (300 MHz, DMSO-d₆) δ ppm: 10.67-10.60 (m, 1H), 7.77 (s, 2H),7.30 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.67 (dd,J=8.9, 2.5 Hz, 1H), 2.94 (p, J=7.0 Hz, 1H), 1.18 (d, J=6.8 Hz, 6H).

Example 2: Synthesis of Compound 2

A 100 mL 3-necked round-bottom flask, maintained with an inertatmosphere of nitrogen, was charged with4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethyl-aniline(450.00 mg, 1.003 mmol, 1.00 eq) in con. HCl (9.60 mL), AcOH (27.40 mL)and H₂O (20.9 mL). To a stirred solution was added NaNO₂ (145.35 mg,2.107 mmol, 2.1 eq) in H₂O (1.8 mL) and dropwise for 45 min at 0° C. Thesecond reaction flask was placed methyl N-(2-cyanoacetyl)carbamate(213.85 mg, 1.505 mmol, 1.50 eq) in H₂O (25.6 mL) and pyridine (9.80 mL)for 10 min at 0° C. The above solution was quickly poured into thesecond reaction flask for 30 min at 0° c. The precipitated solids werecollected by filtration and washed with water and PE. The resultingmixture was concentrated under vacuum. This resulted in ethylN—[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbonyl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamateas a red solid.

To a stirred solution of ethylN—[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbonyl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)oxy)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamate(name generated by Chemdraw) (560.0 mg, 0.910 mmol, 1.00 eq) in DMA(10.00 mL) was added KOAc (178.52 mg, 1.819 mmol, 2.0 eq) in portions atrt. The resulting mixture was stirred for 2 h at 120° C. under nitrogenatmosphere. The reaction was quenched by the addition of water (10 mL)at rt. The resulting mixture was extracted with EA (3×100 mL). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to afford2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(350 mg, 56%) as a red solid.

To a stirred solution of2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)-indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-tri-azine-6-carbo-nitrile(330.00 mg, 1 eq) in THF was added TBAF (1 M in THF) (8.00 mL) at rt.The resulting mixture was stirred for 48 h at 65° C. The resultingmixture was diluted with water (100 mL). The resulting mixture wasextracted with EA (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried over anhydrous Na₂SO₄. After filtration, thefiltrate was concentrated under reduced pressure. Purification afforded2-[4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethyl-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(132.3 mg, 54%) as a yellow solid.

¹H-NMR: (300 MHz, DMSO-d₆) δ ppm: 10.66 (s, 1H), 7.29-7.20 (m, 3H), 7.04(d, J=2.2 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.60 (dd, J=8.8, 2.5 Hz, 1H),2.94 (p, J=6.9 Hz, 1H), 2.10 (s, 6H), 1.19 (d, J=6.8 Hz, 6H).

Example 3: Synthesis of Compound 3

The first reaction flask, to a solution of4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylaniline(480.00 mg, 1.075 mmol, 1.00 eq) in concentrated HCl (9.60 mL), HOAc(28.80 mL) and H₂O (22.4 mL) stirred under nitrogen at 0° C. was addedNaNO₂ (155.72 mg, 2.257 mmol, 2.1 eq) in H₂O (22.4 mL). The reactionmixture was stirred for 45 min at 0° C. The second reaction flask, asolution of ethyl N-(2-cyanoacetyl)carbamate (251.72 mg, 1.612 mmol,1.50 eq) in H₂O (27.2 mL) and pyridine (9.60 mL) was stirred at 0° C.for 10 min. The first reaction flask was quickly poured into the secondreaction flask, the reaction mixture stirred at 0° C. for 30 min. Theprecipitated solids were collected by filtration and washed with water(3×50 mL) and PE (3×50 mL). The resulting mixture was concentrated undervacuum. The crude product was isolated as a yellow solid, 520 mg, 80%pure, 63% yield.

To a solution of ethylN—[(Z)-cyano[2-(4-[[3-isopropyl-1-(4-methyl-benzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)hydrazin-1-ylidene]-carbon-yl]carbamate,which can also be named ethyl(Z)-(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamate(350.00 mg, 0.570 mmol, 1.0 eq) in DMA (8.0 mL) stirred at rt was addedKOAc (111.94 mg, 1.141 mmol, 2.0 eq). The reaction mixture was stirredat 120° C. for 3 h. The reaction was quenched by addition of water (10mL) at rt. The precipitation solids were collected by filtration andwashed with water (3×10 mL). the solids were dried in a vacuum over 2 hat 60° C. to afford2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.The desired product was isolated as a dark orange solid, 250 mg, 80%pure, 62% yield.

To a solution of2-(4-[[3-isopropyl-1-(4-methylbenzenesulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(200.00 mg, 0.352 mmol, 1.00 eq) in THF (5.00 mL) stirred under nitrogenat 0° C. was added TBAF (10.57 mL, 10.570 mmol, 30.00 eq, 1 M in THF).The reaction mixture was stirred at 65° C. for 3 days. The reactionmixture was concentrated under reduced pressure to afford the crudeproduct. The sample was purified to afford2-(4-((3-isopropyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbo-nitrile.as a yellow solid (compound 3, 29.7 mg, 99% pure, 20% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 13.00 (br, 1H), 10.63 (s, 1H),7.19-7.22 (m, 2H), 7.14 (s, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.68-6.71 (m,1H), 4.11 (s, 2H), 3.00-3.04 (m, 1H), 2.27 (s, 6H), 1.24-1.25 (m, 6H).

Example 4: Synthesis of Compound 4

A 50 mL autoclave was charged with2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile(1.00 g, 1.44 mmol, 1.00 eq),dichloro[1,1′-bis(diphenylphosphino)-ferrocene]-palladium(II) (0.11 g,0.144 mmol, 0.10 eq), triethylamine (0.44 g, 4.32 mmol, 3.00 eq),methanol (10 mL). The contents of the autoclave were placed under anatmosphere of carbon monoxide (30 atm). The reaction was stirredovernight at 90° C. The catalysts were filtered out. The filtrate wasconcentrated under reduced pressure. The residue was purified to provide500 mg (yield 67%) of methyl5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzene-sulfonyl)-indole-3-carboxylateas a brown solid.

A 40 mL vial was charged with methyl5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1-(4-methylbenzenesulfonyl)indole-3-carboxyl-ate(400 mg, 0.639 mmol, 1.00 eq), tetrahydrofuran (5 mL),tetrabutylammonium fluoride (6.39 mL, 1 M in tetrahydrofuran, 6.39 mmol,10.0 eq). The reaction was stirred overnight at 65° C. and quenched withwater (10 mL). The resulting solution was extracted with dichloromethane(3×20 mL) and the organic layers were combined, washed with brine (2×10mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified to provide 30.4 mg(yield 15%) of methyl5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxylateas a yellow solid.

¹H NMR (300 MHz, Methanol-d₄) δ ppm: 7.97 (s, 1H), 7.80 (s, 2H),7.41-7.44 (m, 2H), 6.88-6.92 (m, 1H), 3.84 (s, 3H).

Example 5: Synthesis of Compound 5

A 250 mL round-bottom was charged with2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile(1.00 g, 1.759 mmol, 1.00 eq), tetrahydrofuran (20 mL),tetrabutylammonium fluoride (52.78 mL, 1 M in tetrahydrofuran, 52.78mmol, 30.00 eq). The resulting solution stirred overnight at 65° C. andthen quenched with water (150 mL). The resulting mixture was extractedwith ethyl acetate (3×200 mL) and the organic layers were combined,washed with brine (3×200 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified to provide 500 mg (69% yield) of2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid.

To a solution of2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(300 mg, 0.724 mmol, 1.00 eq), trichloroacetic acid (355 mg, 2.17 mmol,3.00 eq) and triethylsilane (337 mg, 2.90 mmol, 4.0 eq) in toluene (10mL) stirred under nitrogen at 100° C. was added cyclopentanone (366 mg,4.35 mmol, 6.00 eq). The reaction mixture stirred overnight at 100° C.and concentrated under reduced pressure. Purification resulting in 20.2mg (6% yield) of2-[3,5-dichloro-4-[(3-cyclopentyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrileas a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 10.77 (s, 1H), 7.81 (s, 2H), 7.30-7.34(m, 1H), 7.13 (d, J=1.8 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 6.64-6.68 (m,1H), 3.06-3.14 (m, 1H), 1.99-2.03 (m, 2H), 1.60-1.78 (m, 6H).

Example 6: Synthesis of Compound 6

A 50 mL round-bottom flask was charged with2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(300 mg, 0.724 mmol, 1.00 eq), trichloroacetic acid (355 mg, 2.17 mmol,3.00 eq), toluene (10.00 mL), triethylsilane (504.10 mg, 4.35 mmol, 6.00eq) under nitrogen. acetophenone (261 mg, 2.17 mmol, 3.00 eq) was addedat 100° C. The resulting solution was stirred overnight at 100° C. andconcentrated under reduced pressure. The residue was dissolved in water(20 mL) and extracted with dichloromethane (3×50 mL). The organic layerswere combined, washed with brine (2×10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Purificationresulted in 63.2 mg (17% yield) of2-(3,5-dichloro-4-[[3-(1-phenylethyl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 10.88 (s, 1H), 7.75 (s, 2H), 7.21-7.29(m, 2H), 7.13-7.21 (m, 4H), 7.06-7.11 (m, 1H), 6.63-6.67 (m, 1H),6.38-6.39 (m, 1H), 4.11-4.18 (m, 1H), 1.56-1.59 (m, 3H).

Example 7: Synthesis of Compound 7

To a stirred solution of2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile(400 mg, 0.576 mmol, 1.00 eq) and phenyl boronic acid (91.3 mg, 0.749mmol, 1.30 eq) in dioxane (4 mL) and water (0.8 mL) was addeddichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) (42.2 mg,0.0580 mmol, 0.10 eq) and potassium carbonate (238.88 mg, 1.728 mmol,3.00 eq) at rt under nitrogen atmosphere. The reaction mixture wasstirred overnight at 90° C. and concentrated under reduced pressure. Theresidue was purified to provide 170 mg (42% yield) of2-(3,5-dichloro-4-[[1-(4-methyl-benzene-sulfonyl)-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a light brown solid.

To a stirred solution of2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfon-yl)-3-phenylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(160 mg, 0.248 mmol, 1.00 eq) in tetrahydrofuran (4 mL) was addedt-butyl-ammonium fluoride (4.96 mL, 1 M in tetrahydrofuran, 4.96 mmol,20.00 eq) at rt under nitrogen atmosphere. Then the reaction mixture wasstirred overnight at 65° C. and quenched with water (10 mL). Theresulting mixture was extracted with ethyl acetate (3×10 mL) and thecombined organic layers were combined, washed with brine (3×20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure. Purification resulted in of2-[3,5-dichloro-4-[(3-phenyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(compound 7, 39 mg, 32%) as a light orange solid.

¹H NMR (300 MHz, Methanol-d₄) δ ppm: 7.78 (s, 2H), 7.50-7.56 (m, 2H),7.49 (s, 1H), 7.35-7.41 (m, 3H), 7.18-7.23 (m, 2H), 681-6.84 (m, 1H).

Example 8: Synthesis of Compound 8

To a solution of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(200.00 mg, 0.460 mmol, 1.00 eq) in HOAc (4.43 mL, 0.074 mmol, 0.16 eq)was added HCl (2.00 mL, 0.055 mmol, 0.12 eq) in portions at rt. Theresulting mixture was stirred overnight at 120° C. under nitrogenatmosphere. The crude product (160 mg) was purified to afford2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (78.3 mg, 38%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ ppm: 13.82 (s, 1H), 12.70 (s, 1H), 12.19(s, 1H), 7.82 (s, 2H), 7.44 (s, 1H), 3.05 (p, J=6.8 Hz, 1H), 1.20 (d,J=6.9 Hz, 6H).

Example 9: Synthesis of Compound 9

To a solution of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(200.00 mg, 0.460 mmol, 1.00 eq) in DMSO (5 mL) was added K₂CO₃ (190.53mg, 1.379 mmol, 3.00 eq) and H₂O₂ (2 mL, 30% in water) in portions at 0°C. The resulting mixture was stirred for 5 h at rt. The reaction wasquenched with saturated Na₂S₂O₃ solution at rt and concentrated underreduced pressure. The residue was purified by reverse flashchromatography with the following conditions (column, C₁₈; mobile phase,ACN in water, 10% to 80% gradient in 30 min) to provide the crudeproduct (150 mg), which was then purified by Prep-HPLC (Column: XBridgePrep OBD C18 Column, Mobile Phase A: Water (10 mM NH₄HCO₃), Mobile PhaseB: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 33% B in 9 min) toafford2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxamide(112.1 mg, 54%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.76 (s, 1H), 12.20 (s, 1H), 8.14 (br,1H), 7.85-7.90 (m, 3H), 7.44 (s, 1H), 3.05 (p, J=6.8 Hz, 1H), 1.20 (d,J=6.8 Hz, 6H).

Example 10: Synthesis of Compound 10

To a solution of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (200.00 mg, 0.440 mmol, 1.00 eq) in t-BuOH (20.00 mL, 210.465 mmol)were added DPPA (375.64 mg, 1.365 mmol, 3.10 eq) and Et₃N (138.12 mg,1.365 mmol, 3.10 eq) in portions at rt. The resulting mixture wasstirred for 24 h at 85° C. under nitrogen atmosphere. The resultingmixture was concentrated. The residue was dissolved in CH₂Cl₂ (100 mL),and was then washed with NH₄C₁ (4×200 mL), NaHCO₃ and brine. Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography, eluted with CH₂Cl₂:MeOH (50:1), toafford tert-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate(110 mg, 48%) as a white solid.

LCMS (ESI, m z): 525 [M+H]⁺.

A solution of t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate(90.0 mg, 1 eq) in 4 N HCl in 1,4-dioxane (5.00 mL) was stirredovernight at rt. The resulting mixture was concentrated. The crudeproduct (70 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C₁₈,Mobile Phase A:Water (10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O), Mobile PhaseB:ACN; Flow rate:60 mL/min; Gradient:10 B to 40 B in 8 min) to afford6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-tri-azine-3,5-dione(18.8 mg, 26%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.26 (s, 1H), 12.18 (s, 1H), 7.85 (s,2H), 7.41 (s, 1H), 6.45 (s, 2H), 2.95-3.10 (m, 1H), 1.19 (d, J=6.9 Hz,6H).

Example 11: Synthesis of Compound 11

To a stirred solution of4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-di-one(430.00 mg, 0.706 mmol, 1.00 eq) and trimethylsilylacetylene (207.96 mg,2.117 mmol, 3.0 eq) in DMF (10 mL) were added CuI (26.88 mg, 0.141 mmol,0.20 eq), Et₃N (214.25 mg, 2.117 mmol, 3.00 eq) and Pd(dppf)Cl₂ (103.28mg, 0.141 mmol, 0.20 eq) in portions at rt under nitrogen atmosphere.The reaction mixture was stirred overnight at 80° C. and quenched withwater (10 mL). The resulting mixture was extracted with EA (3×40 mL).The combined organic layers were washed with water (1×100 mL), driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography to afford4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione(260 mg, 52%) as a off-white solid.

To a stirred solution of4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-1,2,4-triazine-3,5-dione(240.00 mg, 0.383 mmol, 1.00 eq) in DCM (5 mL) was added BBr3 (383.84mg, 1.532 mmol, 4.00 eq) dropwise at 0° C. under nitrogen atmosphere.The reaction was stirred for 4 h at rt and quenched with MeOH (5 mL).The resulting mixture was concentrated under reduced pressure to provide100 mg (crude) of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)-ethynyl]-4H-1,2,4-triazine-3,5-dioneas light brown solid.

To a solution of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[2-(trimethylsilyl)ethynyl]-4H-1,2,4-triazine-3,5-dione(100.00 mg, 0.197 mmol, 1.00 eq) in MeOH (10 mL) was added K₂CO₃ (109.16mg, 0.790 mmol, 4.00 eq) stirred at rt. The reaction mixture was stirredovernight at rt and concentrated under reduced pressure to afford theresidue. Purification resulted in 19.4 mg (yield 22%) of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-ethynyl-4H-1,2,4-triazine-3,5-dioneas a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.75 (s, 1H), 12.23 (s, 1H), 7.77 (s,2H), 7.44 (s, 1H), 4.70 (s, 1H), 3.03-3.10 (m, 1H), 1.20 (d, J=6.8 Hz,6H)

Example 12: Synthesis of Compound 12

To a solution of4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione(300.00 mg, 0.492 mmol, 1.00 eq) and tert-butyl 2-cyanoacetate (208.54mg, 1.477 mmol, 3.0 eq) in DMF (5.00 mg) stirred at rt was added K₂CO₃(272.21 mg, 1.970 mmol, 4.0 eq). The reaction mixture was stirredovernight at 90° C. The reaction mixture was quenched with water (30mL). The resulting mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with brine (2×50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified to provide 190 mg (95% pure)tert-butyl2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate(190 mg, 58%) as a yellow solid.

A 50 mL round-bottom flask was charged with tert-butyl2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-2-cyanoacetate(190.00 mg, 0.284 mmol, 1.00 eq), TsOH (24.43 mg, 0.142 mmol, 0.5 eq)and toluene (5 mL). The resulting solution was stirred for 4 h at 90° C.and quenched with water (10 mL). The resulting mixture was extractedwith dichloromethane (3×50 mL) and the organic layers were combined,washed with brine (2×30 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to provide 190 mg ofcrude (70% pure)2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]acetonitrile(190 mg, 82% yield) as a yellow oil.

To a solution of2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]aceto-nitrile(190.00 mg, 0.334 mmol, 1.00 eq) in DCM (3 mL) stirred under nitrogen at−78° C. was added BBr₃ (501.57 mg, 2.002 mmol, 6.0 eq). The reactionmixture was stirred at rt for 4 h. The reaction mixture was quenchedwith water (10 mL). The resulting solution was extracted withdichloromethane (3×20 mL) and the organic layers were combined, washedwith brine (2×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford the crude product.Purification resulted in 24.9 mg (16% yield) of2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)acetonitrileas a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.71 (s, 1H), 12.20 (s, 1H), 7.81 (s,2H), 7.46 (s, 1H), 4.05 (s, 2H), 3.03-3.07 (m, 1H), 1.11-1.31 (m, 6H).

Example 13: Synthesis of Compound 13

To a solution of4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione(350.00 mg, 0.574 mmol, 1.00 eq) and diethyl malonate (184.02 mg, 1.149mmol, 2.00 eq) in DMSO (5 mL) stirred under nitrogen at rt was addedCs₂CO₃ (561.52 mg, 1.723 mmol, 3.0 eq). The reaction mixture was stirredat 110° C. for 1 h. The reaction mixture was quenched with water (20mL). The resulting solution was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with brine (2×30 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The crude product was diluted withdichloromethane (50 mL) and made the slurry with 100˜200 silica gel mesh(2 g). The sample was purified and the desired product was isolated as ayellow oil. 270 mg, 90% pure, 61% yield.

To a solution of 1,3-diethyl2-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]-propanedioate(250.00 mg, 0.363 mmol, 1.00 eq) in DCM (5.00 mL) stirred under nitrogenat 0° C. was added BBr₃ (363.86 mg, 1.452 mmol, 4.00 eq). The reactionmixture was stirred at rt for 3 h. The reaction mixture was quenchedwith water (15 mL). The resulting solution was extracted withdichloromethane (3×30 mL) and the organic layers were combined, washedwith brine (2×15 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford crude product. No furtherpurification was carried out on this material. The crude product wasisolated as a yellow solid, 210 mg, 70% pure, 71% yield.

To a solution of 1,3-diethyl2-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)propanedioate(210.00 mg, 0.369 mmol, 1.00 eq) in MeOH (5.00 mL) and H₂O (1.00 mL)stirred at rt was added NaOH (147.78 mg, 3.695 mmol, 10.00 eq). Thereaction mixture was stirred at 60° C. for 4 h. The pH value of themixture was adjusted to -5-6 with hydrochloric acid (1 M). The resultingsolution was extracted with dichloromethane (3×30 mL) and the organiclayers were combined, washed with brine (2×10 mL) dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure toafford crude product. The crude product was purified to provide2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetra-hydro-1,2,4-triazin-6-yl)aceticacid. The desired product was isolated as a white solid (54.0 mg, 99.5%pure, 31% yield)

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 7.82 (s, 1H), 7.44 (s, 1H), 3.44 (s,2H), 3.01-3.10 (m, 1H), 1.19-1.24 (m, 6H).

Example 14: Synthesis of Compound 14

To a stirred solution of4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-di-one(400.00 mg, 0.657 mmol, 1.00 eq) in n-BuOH (5 mL) was added methylamine(3.3 mL, 6.565 mmol, 10.00 eq, 2 M in THF) at rt. The reaction mixturewas stirred overnight at 110° C. The reaction mixture was concentratedunder reduced pressure to afford the residue. The residue was purifiedto provide 220 mg (yield 53%) of4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-6-(dimethylamino)-1,2,4-triazine-3,5-dioneas a light yield solid.

To a stirred solution of4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-1,2,4-triazine-3,5-dione(400.00 mg, 0.715 mmol, 1.00 eq) in DCM was added BBr₃ (716.55 mg, 2.860mmol, 4.00 eq) at −78° C. The resulting solution was stirred for 4 h atrt. The reaction mixture was concentrated under reduced pressure toafford the crude product. Purification resulted in 86.9 mg (yield 54%)2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methylamino)-4H-1,2,4-triazine-3,5-dioneas a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 12.99 (s, 1H), 12.23 (s, 1H), 8.82 (d,J=4.8 Hz, 1H), 8.16 (s, 2H), 7.42 (s, 1H), 3.03-3.08 (m, 1H), 2.79 (d,J=4.8 Hz, 3H), 1.20 (d, J=6.9 Hz, 6H).

Example 15: Synthesis Compound 15

To a 50 mL round-bottom flask were added4-[(benzyloxy)methyl]-6-bromo-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione(400.00 mg, 0.657 mmol, 1.00 eq) in n-BuOH (8 mL) and dimethylamine (3.3mL, 6.565 mmol, 10.00 eq, 2 M in THF) at rt. The reaction mixture wasstirred overnight at 110° C. The reaction mixture was concentrated underreduced pressure to afford the residue. The residue was purified toprovide 170 mg (yield 41%) of4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)-oxy]phenyl]-6-(dimethylamino)-1,2,4-triazine-3,5-dioneas a light pink solid.

A 50 mL round bottom flask was charged with4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethyl-amino)-1,2,4-triazine-3,5-dione(160.00 mg, 0.279 mmol, 1.00 eq), DCM (10.00 mL). BBr3 (279.61 mg, 1.116mmol, 4.00 eq) was added at −78° C. The resulting solution was stirred 4h at rt. The reaction mixture was concentrated under reduced pressure toafford the crude product. Purification resulted in 54.3 mg (yield 42%)of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(dimethylamino)-4H-1,2,4-triazine-3,5-dione.

¹HNMR (300 MHz, DMSO-d₆) δ ppm: 7.91 (s, 2H), 7.43 (s, 1H), 3.03-3.10(m, 1H), 2.99 (d, J=8.1 Hz, 6H), 1.20 (d, J=6.9 Hz, 6H).

Example 16: Synthesis of Compounds 16 and 23

Compound 16

To a stirred mixture of3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenylboronicacid (250.00 mg, 0.729 mmol, 1.00 eq),6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione (180.19 mg, 0.875 mmol,1.20 eq), K₂CO₃ (201.48 mg, 1.458 mmol, 2.00 eq) in dioxane (10 mL) andH₂O (1 mL) was added Pd(PPh₃)₄ (168.46 mg, 0.146 mmol, 0.20 eq) undernitrogen atmosphere. The resulting mixture was stirred overnight at 90°C. under nitrogen atmosphere. The reaction was quenched with water (15mL) and extracted with EA (3×15 mL). The combined organic layers werewashed with brine (2×15 mL), dried over anhydrous sodium sulfatefiltered and concentrated under reduced pressure. The crude product wastriturated with EA:PE of 1:5 and MeCN (5 mL), washed with ether (5 mL)to provide the desired product6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-methyl-4H-1,2,4-triazine-3,5-dione(103.8 mg, 34%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 12.45 (br, 1H), 12.21 (s, 1H), 8.10 (s,2H), 7.43 (s, 1H), 3.58 (s, 3H), 3.11-2.97 (m, 1H), 1.20 (d, J=6.9 Hz,6H).

Compound 23

Compound 23 was prepared similarly as described for compound 16, using6-bromo-2-ethyl-4H-1,2,4-triazine-3,5-dione instead of6-bromo-2-methyl-4H-1,2,4-triazine-3,5-dione.

¹H NMR (300 MHz, DMSO-d₆) δ: 12.39 (s, 1H), 12.18 (s, 1H), 8.09 (s, 2H),7.40-7.41 (m, 1H), 3.95-4.03 (m, 2H), 3.00-3.07 (m, 1H), 1.28 (t, J=7.0Hz, 3H), 1.28 (t, J=6.9 Hz, 6H). LCMS (ESI, m z): 438 [M+H]⁺.

Example 17: Synthesis of Compound 17

To a solution of2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(250.0 mg, 0.604 mmol, 1.00 eq) in acetonitrile (4 mL) was addeddropwise chlorosulfonyl isocyanate (102.5 mg, 0.724 mmol, 1.2 eq) inacetonitrile (0.4 mL) at −45° C. under nitrogen. Over the course of theaddition a fine precipitate formed. The mixture was stirred at −45° C.under nitrogen for 10 min. N,N-dimethylformamide (4 mL) was then slowlyadded, and the mixture was allowed to warm to rt and stirred for 2 h.The reaction was quenched by the addition of water/ice (10 mL) at 0° C.The resulting mixture was extracted with ethyl acetate (3×15 mL). Thecombined organic layers were washed with water (3×10 mL), saturatedNaHCO₃, and brine, dried anhydrous sodium sulfate, filtered andevaporated. The residue was purified by Prep-TLC withdichloromethane:methanol (12:1) to afford crude product (160 mg). Thecrude product (160 mg) was purified by Prep-HPLC with the followingconditions (Column: Kinetex EVO C 18 Column, 30*150, 5 μm; Mobile PhaseA: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min;Gradient: 50% B to 50% B in 8 min) to provide5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carbonitrile(75.9 mg, 29% yield) of as a light yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 13.30 (s, 1H), 12.28 (s, 1H), 8.28 (d, J=3.0Hz, 1H), 7.84 (s, 2H), 7.58 (d, J=9.0 Hz, 1H), 6.97-7.01 (m, 1H), 6.86(d, J=2.4 Hz, 1H).

Example 18: Synthesis of Compounds 18 and 19

NaNO₂ (150.8 mg, 2.19 mmol, 2.1 eq) in H₂ (12 mL) was added dropwise toa solution of3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)aniline(350.0 mg, 1.04 mmol, 1.0 eq) in HCl (5.5 mL, cone.), AOH (16 mL) andH₂a (12 mL). The mixture was stirred for 30 min at 0° C. Then thereaction mixture was poured into a solution of ethylN-(2-cyanoacetyl)carbamate (243.8 mg, 1.56 mmol, 1.5 eq) in H₂O (16 mL)and pyridine (5.5 mL) at 0° C. quickly. The resulting mixture wasstirred at 0° C. for 30 min and filtered. The filter cake was washedwith water (2×15 mL) and petroleum ether (2×15 mL) dried under reducedpressure to provide (350 mg, crude) ethylN—[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazin-1-ylidene])carbonyl]carbamate as a yellowsolid.

LCMS (ESI, m z): 503 [M+H]⁺.

To a solution of ethylN—[(E)-cyano([2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]hydrazin-1-ylidene])carbonyl]carbamate(350.00 mg, 0.695 mmol, 1.00 eq) in DMA (20 mL) was added KOAc (341.22mg, 3.477 mmol, 5.00 eq). The resulting mixture was stirred overnight at120° C. and quenched with water (30 mL). The resulting mixture wasextracted with EA (3×40 mL) and the organic layers were combined, washedwith brine (2×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford crude product. The crudeproduct was purified by TLC (Mobile phase: MeOH/DCM=1:7; Rf=0.4;detection: UV) to provide the crude product (180 mg). The product wasseparated by Prep-Chiral-HPLC Column: CHIRALPAK IE, 2*25 cm, 5 m; MobilePhase A: Hex (0.1% FA)—HPLC, Mobile Phase B: EtOH—HPLC; Flow rate: 20mL/min; Gradient: 10% B to 10% B in 21 min. Purification resulted indesired product2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(86.3 mg, 26%) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (br, 1H), 11.00 (s, 1H), 7.82 (d,J=8.7 Hz, 1H), 7.76 (s, 2H), 7.28 (d, J=2.4 Hz, 1H), 6.89 (d, J=8.7 Hz,1H), 2.78-2.95 (m, 1H), 1.13 (d, J=6.6 Hz, 6H).

LCMS (ESI, m z): 457.0 [M+H]⁺.

The reaction also produces the by-product compound2-[3,5-dichloro-4-([3-propyl-1H-pyrrolo[3,2-b]-pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(20.8 mg, 6%) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 13.26 (br, 1H), 11.03 (s, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.76 (s, 2H), 7.33 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.7 Hz,1H), 2.42 (t, J=7.5 Hz, 2H), 1.45-1.58 (m, 2H), 0.77 (t, J=7.5 Hz, 3H).LCMS (ESI, m z): 457.0 [M+H]⁺.

Example 19: Synthesis of Compounds 20, 21 and 22

Compound 21

A 20 mL autoclave was charged with2-(3,5-dichloro-4-[[3-iodo-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile(600.00 mg, 0.864 mmol, 1.00 eq), dimethylamine (2.59 mL, 2 M intetrahydrofuran, 5.185 mmol, 6.00 eq),1,1′-bis(diphenylphosphino)ferrocene (95.47 mg, 0.173 mmol, 0.20 eq),bis(acetonitrile)palladium(II) chloride (22.42 mg, 0.0864 mmol, 0.10eq), triethylamine (262.35 mg, 2.593 mmol, 3.00 eq), toluene (15 mL).The contents of the autoclave were placed under an atmosphere of carbonmonoxide (20 atm). The reaction was stirred overnight at 100° C. andquenched with water (10 mL). The resulting mixture was extracted withethyl acetate (3×15 mL) and the organic layers were combined, washedwith brine (3×15 mL), dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was chromatographed on a C18 column chromatography withCH₃CN:Water (3:2) to provide 300 mg (49% yield) of5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamideas a light brown solid.

LCMS (ESI, m z): 637 [M−H]⁻.

To a stirred solution of5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carbox-amide(200.00 mg, 0.313 mmol, 1.00 eq) in tetrahydrofuran (10 mL) was addedtetrabutylammonium fluoride (1.25 mL, 1 M in tetrahydrofuran, 1.251mmol, 4.00 eq) at room temperature under nitrogen atmosphere. Thereaction mixture was stirred for overnight at 65° C. and quenched withwater (5 mL). The resulting mixture was extracted with dichloromethane(3×20 mL) and the organic layers were combined, washed with brine (5×10mL) and hydrochloric acid (1 M), dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The crude product (150 mg) was purified by Prep-HPLC with the followingconditions (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10 μm;Mobile Phase A: Water (10 mM NH₄HCO₃), Mobile Phase B: ACN; Flow rate:25 mL/min; Gradient: 27% B to 47% B in 7 min) to provide 52 mg (34%yield) of5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1H-indole-3-carboxamideas a light yellow solid.

¹H NMR (300 MHz, Methanol-d₄) δ 7.76 (s, 1H), 7.68 (s, 2H), 7.41 (d,J=9.0 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.90-6.94 (m, 1H), 3.13 (s, 6H).

LCMS (ESI, m z): 485 [M+H]⁺.

Compound 20

Compound 20 was prepared similarly as described for compound 21, using 2eq of isopropylamine instead of 6 eq dimethylamine and reactingovernight at 80° C.

¹H NMR (300 MHz, Methanol-d₄) δ 7.89 (s, 1H), 7.77 (s, 2H), 7.50 (d,J=2.4 Hz, 1H), 7.38 (d, J=9.3 Hz, 1H), 6.87-6.91 (m, 1H), 4.12-4.16 (m,1H), 1.21 (d, J=6.6 Hz, 6H).

LCMS (ESI, m z): 499 [M+H]⁺.

Compound 22

Compound 22 was prepared similarly as described for compound 21, using1.5 eq tetrahydroisoquinoline instead of 6 eq dimethylamine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=8.4 Hz, 3H), 7.45 (d, J=8.8Hz, 1H), 7.15-7.17 (m, 3H), 7.07 (br, 1H), 6.93-6.99 (m, 1H), 6.91-6.92(m, 1H), 4.78 (s, 2H), 3.86 (t, J=6.0 Hz, 2H), 2.87 (t, J=5.8 Hz, 2H).

LCMS: 573 [M+H]⁺.

Example 20: Synthesis of Compounds 24, 25 and 26

Compound 25

To a solution of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (500 mg, 1.101 mmol, 1.00 eq) and N,N-diisopropylethylamine (298.77mg, 2.312 mmol, 2.10 eq) in tetrahydrofuran (30 mL) at 0° C. undernitrogen was added ethyl chloroformate (126.62 mg, 1.167 mmol, 1.06 eq)dropwise. The mixture was stirred for 1 h at room temperature andtreated dropwise with a solution of sodium borohydride (124.94 mg, 3.302mmol, 3.00 eq) in water (2 mL) at 0° C. The resulting solution wasstirred overnight at room temperature and then quenched slowly withsaturated NaHCO₃ solution (10 mL). The resulting mixture was extractedwith chloroform/isopropanol (3/1) (5×30 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to provide the crude product. The crude product(400 mg) was purified by preparative HPLC using the following gradientconditions: Column: XSelect CSH Prep C18 OBD Column, 5 m, 19*150 mm;Mobile Phase A: Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN;Flow rate: 25 mL/min; Gradient: 19% B to 31% B in 8 min), resulting inof2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymeth-yl)-4H-1,2,4-triazine-3,5-dione(100.6 mg, 21% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.48 (br, 1H), 12.22 (br, 1H), 7.86 (s,2H), 7.44 (s, 1H), 5.30 (t, J=6.0 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H),3.02-3.11 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

LCMS (ESI, m z): 440 [M+H]⁺.

Compound 24

A 50-mL round-bottom flask was charged with2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2,4-triazine-3,5-dione(1.60 g, 3.634 mmol, 1.00 eq), acetonitrile (15 mL). Phosphorustribromide (0.3 mL) was added at 0° C. under nitrogen. The resultingsolution was stirred for 1 h at 75° C. The mixture was cooled to roomtemperature and then quenched with saturated NaHCO₃ aqueous (10 mL). Theresulting mixture was extracted with ethyl acetate (3×15 mL) and theorganic layers were combined, washed with brine (1×30 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to provide 1.1 g (39% yield) of6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneas a yellow solid.

LCMS (ESI, m z): 502 [M+H]⁺.

A 50-mL round-bottom flask was charged with6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-tri-azine-3,5-dione(400 mg, 0.795 mmol, 1.00 eq), methylamine (1.2 mL, 2 M intetrahydrofuran, 2.385 mmol, 3.00 eq) and N,N-dimethylformamide (8 mL).The mixture was stirred for 1 h at 70° C. The mixture was cooled to roomtemperature and diluted with water (5 mL). At this time, it wasacidified by the addition of 1 N hydrochloric acid (5 mL) and wasextracted with ethyl acetate (3×10 mL). The organic layer was discarded.The aqueous layer was made basic by the addition saturated NaHCO₃solution (15 mL) and extracted with a mixture solution ofchloroform:isopropanol of 3:1 (5×30 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to provide the crude product. The crude product(300 mg) was purified by preparative HPLC using the following gradientconditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; MobilePhase A: Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 17% B to 35% B in 8 min. Purificationresulted in of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[(methylamino)methyl]-4H-1,2,4-triazine-3,5-dione(64.8 mg, 18% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.23(br, 1H), 7.88 (s, 2H), 7.43 (s, 1H), 3.83 (s, 2H), 3.01-3.19 (m, 1H),2.51 (s, 3H), 1.20 (d, J=6.9 Hz, 6H). LCMS (ESI, m z): 453 [M+H]⁺.

Compound 26

Compound 26 was prepared similarly as described for compound 24, usingdimethylamine instead methylamine and reacting at 60° C. for 1 h. ¹H NMR(300 MHz, DMSO-d₆) δ 12.21 (br, 1H), 7.80 (s, 2H), 7.45 (s, 1H), 3.37(br, 2H), 3.03-3.08 (m, 1H), 2.25 (s, 6H), 1.20 (d, J=6.9 Hz, 6H). LCMS(ESI, m z): 467 [M+H]⁺.

Example 21: Synthesis of Compound 27

A 100-mL round-bottom flask was charged with6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(400.00 mg, 0.795 mmol, 1.00 eq), imidazole (64.95 mg, 0.954 mmol, 1.20eq), potassium carbonate (219.75 mg, 1.590 mmol, 2.00 eq) andN,N-dimethylformamide (8 mL). The mixture was stirred for 1 h at 70° C.and was subsequently cooled to room temperature and diluted with water(5 mL). At this time, it was acidified by the addition of 1 Nhydrochloric acid (5 mL) and was extracted with ethyl acetate (3×10 mL).The organic layer was discarded. The aqueous layer was made basic by theaddition saturated NaHCO₃ solution (15 mL) and extracted with a mixtureof chloroform:isopropanol of 3:1 (5×30 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to provide the crude product. The crude product(150 mg) was purified by preparative HPLC using the following gradientconditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 m; MobilePhase A: Water (10 mM NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flowrate: 60 mL/min; Gradient: 19% B to 37% B in 8 min; Purificationresulted in of2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(imidazol-1-ylmethyl)-4H-1,2,4-triazine-3,5-dione(14.5 mg, 4% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 7.74 (s, 2H), 7.69 (s, 1H),7.43 (s, 1H), 7.21 (s, 1H), 6.90 (s, 1H), 5.15 (s, 2H), 3.02-3.09 (m,1H), 1.19 (d, J=6.9 Hz, 6H).

LCMS (ESI, m z): 490 [M+H]⁺.

Example 22. Synthesis of Compound 28

To a stirred mixture of4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2H-1,2,4-triazine-3,5-dione(310 mg, 0.569 mmol, 1.00 eq) and K₂CO₃ (630 mg, 4.56 mmol, 8.00 eq) inDMF (20 mL) was bubbled with difluorochloromethane for 4 h and themixture was stirred for 5 h at 50° C. The reaction was quenched by theaddition of water (50 mL). The resulting mixture was extracted with EA(3×30 mL). The combined organic layers were washed with water (150 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(eluting with PE:EA of 2:1) to afford 230 mg (65% yield) of4-[(benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxypyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazine-3,5-dioneas a light yellow solid.

LCMS (ESI, m z): 594 [M+H]⁺.

4-[(Benzyloxy)methyl]-6-[3,5-dichloro-4-[(5-isopropyl-6-methoxy-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-1,2,4-triazine-3,5-dione(230 mg, 0.387 mmol, 1.00 eq) in a solution of hydrogen chloride (4 mL,4M in 1,4-dioxane) was stirred for 2 h at 60° C. After cooled down to25° C., the resulting mixture was concentrated under vacuum. The residuewas then diluted with DCM (5 mL) and added a solution of BBr₃ (1.5 mL, 1M in DCM) dropwise at 25° C. The final reaction mixture was stirred for45 min at 25° C. The reaction was quenched by the addition of water (1mL). The resulting mixture was concentrated under reduced pressure. Theresidue was purified by reverse phase chromatography (column: C₁₈ silicagel; Mobile phase, A: water (containing 10 mM NH₄HCO₃) and B: ACN (0% to50% over 15 min); Detector: UV 220/254 nm). The product fractions werelyophilized to afford 113.4 mg (63% yield) of6-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-2-(difluoromethyl)-4H-1,2,4-triazine-3,5-dioneas a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.78 (br s, 1H), 12.22 (br s, 1H),7.99 (s, 2H), 7.83 (t, J=57.2 Hz, 1H), 7.45 (s, 1H), 3.13-2.98 (m, 1H),1.20 (d, J=7.2 Hz, 6H). LCMS (ESI, m z): 460 [M+H]⁺.

Example 23 Synthesis of Compound 29

A 50-mL round-bottom flask was charged with6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(400 mg, 0.795 mmol, 1.00 eq), N,N-dimethylformamide (8 mL) undernitrogen. Sodium methylate (0.50 mL, 30% w/w in methanol) was added at0° C. The mixture was stirred for 1 h at 0° C. The mixture was acidifiedby the addition of 1 N hydrochloric acid (5 mL) and was extracted withethyl acetate (3×15 mL). The organic layer was washed with brine (2×30mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn with dichloromethane/methanol (10/1) to provide the crude product(150 mg) and then was purified by preparative HPLC using the followinggradient conditions: Column: XSelect CSH Prep C18 OBD Column, 5 μm,19*150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flowrate: 25 mL/min; Gradient: 31% B to 51% B in 8 min; Purificationresulted in2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(methoxymethyl)-4H-1,2,4-triazine-3,5-dione(26.2 mg, 7% yield) of as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 12.53 (s, 1H), 12.22 (s, 1H), 7.80 (s, 2H),7.45 (s, 1H), 4.32 (s, 2H), 3.03-3.07 (m, 1H), 2.48 (s, 3H), 1.20 (d,J=6.9 Hz, 6H).

LCMS (ESI, m z): 454 [M+H]⁺.

Example 24 Synthesis of Compound 30

A 100-mL round-bottom flask was charged with2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile(300.00 mg, 0.689 mmol, 1.00 eq), concentrated hydrochloric acid (2 mL),Pd/C (30.00 mg, 0.282 mmol, 0.41 eq), methanol (30.00 mL, 0.936 mmol,1.36 eq) under hydrogen. The resulting solution was stirred overnight atroom temperature and then filtered through celite. The celite pad waswashed with methanol (5×30 mL), the filtrate was collected andconcentrated under reduced pressure. The residue was diluted withsaturated NaHCO₃ solution (10 ml) and extracted withchloroform:isopropanol (3:1) (5×15 mL) and the organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The crude product (300 mg) was purified bypreparative HPLC using the following gradient conditions: Column:Kinetex EVO C18 Column, 30*150, 5 m; Mobile Phase A: Water (10 mMNH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 25 mL/min;Gradient: 5% B to 30% B in 9 min. Purification resulted in6-(aminomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(29.6 mg, 10% yield) of a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.93(s, 2H), 7.42 (s, 1H), 3.84 (br, 2H), 3.02-3.07 (m, 1H), 1.20 (d, J=6.9Hz, 6H). LCMS (ESI, m z): 439 [M+H]⁺.

Example 25. Synthesis of Compound 31

To a mixture of4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-aniline(70 mg, 156.39 μmol, 1 eq), con. HCl (87.97 μL, 6.75 eq) in H₂O (1 mL)was added dropwise a solution of sodium nitrite (14.84 mg, 215.04 μmol,1.38 eq) in H₂O (1 mL) while maintaining the temperature below 0° C.After the completion of addition, the reaction mixture was stirred for0.5 h. A mixture of ethyl N-(2-cyanoacetyl)carbamate (27.47 mg, 175.94μmol, 1.13 eq) and NaOAc (43.30 mg, 527.83 μmol, 3.38 eq) in EtOH (3 mL)was added drop-wise to the resulting diazonium salt solution below 0° C.and stirred for a further 2 h. The reaction mixture (combined withanother 50 mg batch) was diluted with H₂O (10 mL), adjusted to pH 7˜8 bysat. aq. NaHCO₃, then extracted with EA (50 mL×3). The combined organiclayers were washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated to give a residue The residue was purified byflash silica gel chromatography (Ethyl acetate in Petroleum ether=0˜35%)to give ethylN-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazono]acetyl]carbamate(75 mg, 31% yield) as a yellow solid.

A mixture of ethylN-[(2E)-2-cyano-2-[[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]hydrazono]-acetyl]carbamate(55 mg, 89.47 μmol, 1 eq) and NaOAc (36.70 mg, 447.36 μmol, 5 eq) inAcOH (5 mL) was stirred at 130° C. for 5 h. AcOH was removed underreduced pressure, the residue was diluted with H₂O (50 mL), adjusted topH 7˜8 by sat. aq. NaHCO₃, then extracted with EA (50 mL×3). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(65 mg) as a yellow solid, which was directly used in the next stepwithout further purification.

To a solution of2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(60 mg, 105.51 μmol, 1 eq) in THF (5 mL) was added TBAF (1 M in THF,2.53 mL, 24 eq) in one portion at 20° C. Then the resulting mixture wasstirred at 65° C. for 8 h under N₂. LCMS showed the reaction wascomplete. The mixture was diluted with H₂O (100 mL) and extracted withEA (50 mL×3). The combined organic layers were washed with sat. aq.NH₄Cl (100 mL×3), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give crude product, which was purified byprep. HPLC [Column: Welch Xtimate C18 150*30 mm, 5 μm; Mobile phase:from 15% ACN in water (0.225% FA) to 45% ACN in water (0.225% FA)] togive2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(25 mg, 56% yield, 98.3% purity) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.11-12.66 (m, 1H), 10.83 (br s, 1H), 7.57(d, J=8.4 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.15 (s, 2H), 6.70 (d, J=8.4Hz, 1H), 4.24 (s, 2H), 3.20 (td, J=6.8, 13.7 Hz, 1H), 2.39 (s, 6H), 1.33(d, J=6.9 Hz, 6H).

Example 26. Synthesis of Compound 32

A solution of NaNO₂ (2.1 eq, 45 mg) in water (6.5 mL) was added to asolution of 3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline (1eq, 100 mg, 0.31 mmol) in HCl 37% (106 eq, 2.7 mL), acetic acid (8.3 mL)and water (6.5 mL) at 0° C. under N₂. The reaction mixture was stirredat 0° C. for 1 h. In parallel, a solution of ethylN-(2-cyanoacetyl)carbamate (1.5 eq, 73 mg) in water (7.8 mL) andpyridine (2.7 mL) was stirred at 0° C. for 15 min. The first reactionmixture was quickly added to the second one. The resulting reactionmixture was stirred at 0° C. for 2 h.

The precipitate was filtered and washed with water and petroleum etherto giveethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)-phenyl)hydrazineylidene)acetyl)carbamate(13 mg) as a yellow solid. The filtrate was extracted with DCM (3×50 mL)and the combined organic phases were dried over MgSO₄, filtered andevaporated to dryness to giveethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)hydrazineylidene)acetyl)-carbamate(225 mg) as a yellow solid. The crude was used as such in the next step.

Sodium acetate (4 eq, 102 mg) was added to a solution ofethyl-(2-cyano-2-(2-(3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)phenyl)hydrazineylid-ene)acetyl)carbamate(1 eq, 152 mg, 0.31 mmol) in acetic acid (5 mL) under N₂. The reactionmixture was heated to reflux for 4 h and then cooled to 0° C., water (10mL) was added and the mixture was stirred for 30 min. Then, theprecipitate was filtered, washed with water and petroleum ether andpurified by flash chromatography on silica gel (0 to 10% MeOH in DCM) togive 40 mg of a red solid which was further triturated in Et₂O and iPr₂Oto give compound 32 (20 mg, 15%) as an orange solid. ¹H-NMR (DMSO, 400MHz): 0.83 (t, J=2.5 Hz, 3H); 1.27 (br, s, 4H); 1.63-1.70 (quint, J=7.7Hz, 2H); 2.28 (s, 6H); 2.80 (t, J=7.2 Hz, 2H); 4.15 (s, 2H); 7.00 (d,J=8.8 Hz, 1H); 7.18 (s, 2H); 7.27 (s, 1H); 7.35 (d, J=8.8 Hz, 1H); 12.51(s, 1H); 12.99 (s, 1H)

Example 27. Synthesis of Compound 33

A 50 mL round-bottom flask was charged with2-[3,5-dichloro-4-[(5-iso-propyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-(hydroxymethyl)-4H-1,2,4-triazine-3,5-dione(1.60 g, 3.63 mmol), CH₃CN (15 mL). PBr₃ (0.3 mL) was added at 0° C.under N₂. The resulting solution was stirred for 1 h at 75° C. Themixture was cooled to rt and then quenched with NaHCO₃ (sat., aq., 10mL). The resulting mixture was extracted with EA (3×15 mL) and theorganic layers were combined, washed with brine (1×30 mL), dried overanhyd. Na₂SO₄, filtered and concentrated under reduced pressure toprovide6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneas a yellow solid (1.1 g, 39%).

A 50 mL round-bottom flask was charged with6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(300 mg, 0.60 mmol), DMF (8 mL). NaSCH₃ (125 mg, 1.79 mmol) was added at0° C. The mixture was acidified by the addition of 1 N aq. HCl (5 mL)and was extracted with EA (3×15 mL). The organic layers were combined,washed with brine (2×50 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on asilica gel column with PE:EA (1:3) to provide the crude product (150 mg)and then was purified by preparative HPLC. Purification resulted in2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-6-[(methylsulfanyl)-methyl]-4H-1,2,4-triazine-3,5-dioneas an off-white solid (32.9 mg, 12%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.55(br, 1H), 12.21 (s, 1H), 7.81 (s, 2H), 7.45 (s, 1H), 3.54 (s, 2H),3.01-3.10 (m, 1H), 2.11 (s, 3H), 1.20 (d, J=6.6 Hz, 6H). LCMS (ESI, mz): 470 [M+H]⁺.

Example 28. Synthesis of Compound 34

A 50 mL round-bottom flask was charged with6-(bromomethyl)-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(480 mg, 0.954 mmol), DMF (8 mL), CH₃SO₂Na (292 mg, 2.86 mmol). Themixture was stirred for 1 h at 60° C. The mixture was acidified by theaddition of HCl (aq., 1N, 5 mL) and was extracted with EA (3×15 mL). Theorganic layers were combined, washed with brine (2×50 mL), dried overanhyd. Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified on a silica gel column with DCM:MeOH (10:1) toprovide the crude product and then was purified by preparative HPLC toafford2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-6-(methanesulfonylmethyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (70.8 mg, 15%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.74 (br, 1H), 12.22 (s, 1H), 7.84 (s, 2H),7.45 (s, 1H), 4.48 (s, 2H), 3.01-3.11 (m, 4H), 1.20 (d, J=6.9 Hz, 6H).LCMS (ESI, m z): 502 [M+H]⁺.

Example 29. Synthesis of Compound 35

A 500 mL round-bottom was charged with 3-methyl-4-nitrophenol (4.50 g,29.4 mmol), benzyltrimethylammonium tetrachloroiodate (24.6 g, 58.8mmol), AcOH (600 mL). The reaction was stirred 18 h at 70° C. The solidswere removed by filtration and washed with AcOH (300 mL). The organiclayers were concentrated under reduced pressure. The residue wasdissolved in EA:water (500 mL:250 mL). The organic layer was separated,washed with brine (2×200 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified on asilica gel column with EA:PE (4:94) to provide2,6-dichloro-3-methyl-4-nitrophenol as a brown solid (4.9 g, 64%).

A 250 mL vial was charged with 2,6-dichloro-3-methyl-4-nitrophenol (5.00g, 22.5 mmol), Fe powder (6.29 g, 113 mmol), NH₄C₁ (9.64 g, 180 mmol),EtOH (50 mL), and water (25 mL). The reaction was stirred overnight at50° C. The solids were removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified on asilica gel with EA:PE (2:5) to provide4-amino-2,6-dichloro-3-methylphenol as a light brown solid (3.45 g,59%).

3,5-Dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-2-methylanilinewas prepared similarly as described for3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline toafford a brown solid (3.9 g, 73%), starting from4-amino-2,6-dichloro-3-methylphenol.

6-(4-Amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2H-pyridazin-3-onewas prepared similarly as described for6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one, startingfrom 4-amino-2,6-dichloro-3-methylphenol, to afford an off-white solid(2.5 g, 56%).

Ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamatewas prepared similarly as described for ethyl(E)-(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamateto afford an orange solid (140 mg, 72%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(compound 35-A) was prepared similarly as described for2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile,to afford a brown solid (2.1 g, 64%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid was prepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid to afford a brown solid (1.0 g, 52%).

t-Butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamatewas prepared similarly as described for t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamateto afford a brown solid (600 mg, 71%).

A 100 mL round-bottom flask was charged witht-butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate(600 mg, 1.11 mmol), DCM (15.0 mL). TFA (5 mL) was added dropwise at 0°C. The reaction was stirred overnight at rt and concentrated underreduced pressure. The residue was dissolved with EA (50 mL). The pH ofthe solution was adjusted to 8 with NaHCO₃ (sat., aq.), then extractedwith EA (3×20 mL), the organic layers were combined, washed with brine(2×10 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to provide6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]-4H-1,2,4-triazine-3,5-dione(compound 35) as a white solid (105 mg, 39%). ¹H NMR (300 MHz, DMSO-d₆)δ 12.18 (br, 2H), 7.72 (s, 1H), 7.45 (s, 1H), 6.39 (br, 2H), 3.01-3.10(m, 1H), 2.20 (s, 3H), 1.20 (d, J=6.9 Hz, 6H). LCMS (ESI, m z): 439[M+H]⁺.

Example 30. Synthesis of Compound 36

6-[(4-Amino-2,6-dichlorophenyl)methyl]-4-isopropyl-2H-pyridazin-3-onewas prepared according to the literature procedure (J. Med. Chem. 2014,57, 3912-3923) to afford a yellow solid (1.9 g, 50%).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)hydrazineylidene)acetyl)carbamatewas prepared similarly as described for ethyl(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamateto afford a yellow solid (659 mg, 86%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewas prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileto afford off-white solid (1.3 g, 86%).

2-[3,5-Dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid was prepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid to afford a yellow oil (800 mg, 48%).

t-Butyl-N-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamatewas prepared similarly as described for t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamateto afford a yellow solid (600 mg, 65%).

6-Amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)methyl]-phenyl]-4H-1,2,4-triazine-3,5-dionewas prepared similarly as described for6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H-1,2,4-triazine-3,5-dioneto afford a white solid (227 mg, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.76(s, 2H), 7.30 (s, 1H), 6.52 (br, 2H), 4.24 (s, 2H), 2.98-3.02 (m, 1H),1.15 (d, J=6.9 Hz, 6H). LCMS (ESI, m z): 423 [M+H]⁺.

Example 31. Synthesis of Compound 37

4-Amino-2-chloro-6-methylphenol was prepared similarly as described inWO2004014382 to afford a brown solid (10.8 g, 88%).

3-Chloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]-5-methylaniline wasprepared similarly as described for3,5-dichloro-4-[(6-chloro-5-isopropyl-pyridazin-3-yl)oxy]-aniline toafford a brown semi-solid (9.5 g, 68%).

6-(4-Amino-2-chloro-6-methylphenoxy)-4-isopropyl-2H-pyridazin-3-one wasprepared similarly as described for6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one to afforda pink solid (6.5 g, 68%).

Ethyl(2-(2-(3-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-5-methylphenyl)hydrazineylidene)-2-cyanoacetyl)carbamatewas prepared similarly as described for ethyl(2-cyano-2-(2-(4-((3-isopropyl-1-tosyl-1H-indol-5-yl)methyl)-3,5-dimethylphenyl)hydrazineylidene)acetyl)carbamateto afford a yellow solid (4.56 g, 75%).

2-[3-Chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewas prepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileto afford a light yellow solid (2.3 g, 53%).

2-[3-Chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid was prepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid to afford a white solid (880 mg, 75%).

t-Butyl-N-(2-[3-chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methylphenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamatewas prepared similarly as described for t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamateto afford a white solid (790 mg, 70%).

6-Amino-2-[3-chloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-5-methyl-phenyl]-4H-1,2,4-triazine-3,5-dionewas prepared similarly as described for6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H-1,2,4-triazine-3,5-dioneto afford a white solid (100 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.18(br, 1H), 12.10 (s, 1H), 7.58-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.34-7.37(m, 1H), 6.41 (s, 2H), 3.08-2.99 (m, 1H), 2.18 (s, 3H), 1.19 (d, J=6.8Hz, 6H). LCMS (ESI, m z): 405.0 [M+H]⁺.

Example 32. Synthesis of Compound 38

6-Amino-2-[4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-3,5-dimethylphenyl]-4H-1,2,4-triazine-3,5-dionewas prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneto afford a white solid (238 mg, 54%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.10(br, 1H), 12.00 (br, 1H), 7.30 (s, 1H), 7.25 (s, 2H), 6.32 (br, 2H),3.01-3.09 (m, 1H), 2.10 (s, 6H), 1.20 (d, J=6.6 Hz, 6H). LCMS (ESI, mz): 385 [M+H]⁺.

Example 33. Synthesis of Compounds 39-A, and 39-B

3,6-Dichloro-4-(sec-butyl)pyridazine was prepared similarly as describedfor 3,6-dichloro-4-isopropylpyridazine (see also Samaritoni, J. G.Homolytic alkylation of 3,6-dichloropyridazine. Org. Prep. Proced. Int.1988, 20, 117-121) to afford a yellow oil (23.3 g, 79%).

To a mixture of 3,6-dichloro-4-(sec-butyl)pyridazine (7.00 g, 34.1 mmol)and 4-amino-2,6-dichlorophenol (6.68 g, 37.6 mmol) in DMSO (70 mL) wasadded K₂CO₃ (14.2 g, 103 mmol) and CuI (1.95 g, 10.2 mmol). Theresulting mixture was stirred overnight at 90° C. under N₂. The solidswere removed by filtration and the filtrate was quenched with NH₄C₁(sat. aq., 150 mL). The resulting mixture was extracted with EA (3×200mL) and the organic layers were combined, washed with brine (2×150 mL),dried over anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to afford crudeproduct. The sample was purified by silica column chromatography, elutedwith EA:PE (0˜40% over 20 min). Fractions were collected, combined, andconcentrated under reduced pressure to provide3,5-dichloro-4-[[6-chloro-5-(sec-butyl)pyridazin-3-yl]oxy]aniline as abrown semi-solid (10 g, 72%).

A mixture of3,5-dichloro-4-[[6-chloro-5-(sec-butyl)pyridazin-3-yl]oxy]-aniline (10g, 28.9 mmol) and NaOAc (8.28 g, 101 mmol) in AcOH (100 mL) was stirredovernight at 100° C. The mixture was concentrated under reduced pressureto remove AcOH. The residue was diluted with water (100 mL) and the pHwas adjusted to 8 with NaOH (aq., 1 M). The mixture was extracted withEA (3×150 mL) and the organic layers were combined, dried over anhyd.Na₂SO₄, filtered and concentrated under reduced pressure. The residuewas dissolved in MeOH (100 mL) and NaOH (100 mL, 1 M aq.) and theresulting mixture was stirred overnight at 100° C. The mixture wasconcentrated under reduced pressure to remove MeOH. The resultingmixture was extracted with EA (3×150 mL) and the organic layers werecombined, washed with brine (2×100 mL), dried over anhyd. Na₂SO₄,filtered and concentrated under reduced pressure to afford crudeproduct. The sample was purified by silica column chromatography(EA:PE=0˜70% over 20 min). Fractions were collected, combined, andconcentrated under reduced pressure to provide6-(4-amino-2,6-dichlorophenoxy)-4-(sec-butyl)-2H-pyridazin-3-one as alight yellow solid (5.95 g, 60%).

Ethyl(2-(2-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)hydrazineylidene)-2-cyanoacetyl)carbamate,a yellow solid (4.63 g, 77%), was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

A mixture of ethyl(2-(2-(4-((5-(sec-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)hydrazineylidene)-2-cyanoacetyl)carbamate(4.40 g, 8.88 mmol) and NaOAc (3.64 g, 44.4 mmol) in AcOH (50 mL) wasstirred for 2 h at 120° C. The mixture was poured into water (100 mL)and the crude product was obtained by filtration. The sample waspurified by column chromatography (CH₃OH: DCM=0˜15% over 20 min).Fractions were collected, combined, and concentrated under reducedpressure to provide2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid (2.27 g, 52%).

A mixture of2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(1.00 g, 2.23 mmol) in conc. HCl (5 mL) and AcOH (10 mL) was stirred for2 h at 120° C. The mixture was poured into water (20 mL) and the desiredproduct2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid was obtained by filtration as a white solid (860 mg, 78%).

To a mixture of2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (860 mg, 1.84 mmol) in tBuOH (15.0 mL) was added DPPA (1.52 g, 5.52mmol) and NEt₃ (743 mg, 7.35 mmol). The resulting mixture was stirredovernight at 85° C. under N₂, then concentrated under reduced pressure.The residue was diluted with DCM (50 mL), washed with brine (30 mL),dried over anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to afford crude productthat was purified by column chromatography and eluted with MeOH:DCM(0˜7% over 20 min). Fractions were concentrated under reduced pressureto provide racemict-butyl-N-[2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]oxy]-phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamateas a white solid (700 mg, 67%).

t-Butyl-N-[2-(3,5-dichloro-4-[[6-oxo-5-(sec-butyl)-1H-pyridazin-3-yl]-oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(500 mg, 0.927 mmol) was further purified by preparatory SFC-HPLC(Column: Reg-AD, 30×250 mm, 5 μm; Mobile Phase A: CO₂, Mobile Phase B:EtOH (8 mmol/L NH₃.MeOH)-HPLC; Flow rate: 50 mL/min; Gradient: 50% B;220 nm; Injection Volume: 4 mL; Number Of Runs: 11). Purificationresulted in enantiomer 1 as white solid (130 mg, 26%, Rt: 5.79 min), andenantiomer 2 as a white solid (Rt: 6.97 min, 190 mg, 37%).

The boc group of each enantiomer was separately deprotected in DCM (10mL) and TFA (3 mL). The resulting mixtures were stirred for 4 h at rtand concentrated under reduced pressure. The solvent was removed underreduced pressure, the mixtures were diluted with EA (30 mL), washed withNaHCO₃ (sat., aq., 20 mL), dried over anhyd. Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure to afford the crude product.

Compound 39-A (corresponding to enantiomer 1) was purified bypreparative HPLC (Column: Xselect CSH OBD Column 30×150 mm 5 μm; MobilePhase A:Water (10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: ACN;Flow rate: 60 mL/min; Gradient: 23 B to 43 B in 7 min; 220 nm; RT: 5.32min) to afford a white solid (49.6 mg, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ11.95-12.52 (m, 2H), 7.86 (s, 2H), 7.42 (s, 1H), 6.52 (s, 2H), 2.86-2.94(m, 1H), 1.64-1.74 (m, 1H), 1.45-1.56 (m, 1H), 1.17 (d, J=6.9 Hz, 3H),0.86 (t, J=7.5 Hz, 3H). LCMS (ESI, m z): 439.0 [M+H]⁺.

Compound 39-B (corresponding to enantiomer 2) was triturated withEA:MeOH (5 mL:1 mL) to provide the desired product as an off-white solid(67.5 mg, 42%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.19-12.28 (m, 2H), 7.86(s, 2H), 7.42 (s, 1H), 6.53 (s, 2H), 2.83-2.94 (m, 1H), 1.61-1.77 (m,1H), 1.43-1.58 (m, 1H), 1.18 (d, J=6.9 Hz, 3H), 0.86 (t, J=7.4 Hz, 3H).LCMS (ESI, m z): 439.0 [M+H]⁺.

SFC Analysis on compounds 39-A, and 39-B: Column name: Enantiocel C3-3,4.6×100 mm, 3 μm. Co-Solvent: 20% EtOH (0.1% DEA). Flow (mL/min): 4.Temperature: 35° C. Detector: 220 nm. 39-A: Rt=2.947 min. 39-B: Rt=3.269min.

Example 34. Synthesis of Compounds 40-A and 40

3,6-dichloro-4-cyclobutylpyridazine was prepared similarly as describedfor 3,6-dichloro-4-isopropylpyridazine to afford a colorless oil (12 g,38%).

3,5-dichloro-4-[(6-chloro-5-cyclobutylpyridazin-3-yl)oxy]aniline wasprepared similarly as described for3,5-dichloro-4-[[6-chloro-5-(sec-butyl)pyridazin-3-yl]oxy]aniline toafford a yellow solid (3.07 g, 34%).

A stirred mixture of3,5-dichloro-4-[(6-chloro-5-cyclobutylpyridazin-3-yl)oxy]aniline (2.52g, 7.31 mmol), NaOAc (2.10 g, 25.6 mmol) in AcOH (25 mL) was stirredovernight at 100° C. The resulting mixture was concentrated underreduced pressure to remove AcOH. The residue was diluted with water (30mL) and the pH was adjusted to 8 with NaOH (aq., 1 M). The mixture wasextracted with EA (3×60 mL) and the organic layers were combined, driedover anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue wasdissolved in MeOH (25 mL) and NaOH solution (25 mL, 1 M aq.) and theresulting mixture was stirred overnight at 120° C. The mixture wasconcentrated under reduced pressure. The resulting mixture was extractedwith EA (3×60 mL), the organic layers were combined, washed with brine(2×40 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure toafford 6-(4-amino-2,6-dichlorophenoxy)-4-cyclobutyl-2H-pyridazin-3-one(2.27 g, crude) as a brown solid.

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydro-pyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(2.61 g, crude yellow solid) was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

To a stirred mixture of ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(2.50 g, 5.07 mmol) in DMA (25 mL) was added KOAc (1.99 g, 20.3 mmol) inportions at rt. The resulting mixture was stirred for 5 h at 120° C.under N₂. The reaction was quenched with water (200 mL) and extractedwith EA (3×150 mL), and the organic layers were combined, dried overanhyd. Na₂SO₄, the solids were removed by filtration and the filtratewas concentrated under reduced pressure. The crude product was purifiedby silica gel column chromatography, eluted with DCM:MeOH (9:1) toafford2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a brown solid (compound 40-A, 2.1 g, 84%). ¹H NMR (300 MHz, DMSO-d₆)δ 13.27 (br, 1H), 12.19 (s, 1H), 7.79 (s, 2H), 7.49-7.51 (m, 1H),3.50-3.62 (m, 1H), 1.93-2.34 (m, 5H), 1.75-1.88 (m, 1H).

To a stirred mixture of2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(1.30 g, 2.91 mmol) in AcOH (12 mL) was added HCl (6 mL) dropwise at rt.The resulting mixture was stirred for 2 h at 120° C. The resultingmixture was concentrated under reduced pressure to remove AcOH. The pHof the mixture was adjusted to 8 with Na₂CO₃ (sat., aq.). The resultingmixture was extracted with EA (3×50 mL). The pH of the mixture wasadjusted to 5 with HCl (1 M). The resulting mixture was extracted withEA (3×50 mL) and the organic layers were combined, dried over anhyd.Na₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure to afford2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (1.0 g, crude) as a yellow solid. The crude product was used in thenext step without further purification.

To a stirred solution of2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (800 mg, 1.72 mmol) in t-BuOH (30 mL) was added DPPA (1.42 g, 5.15mmol) and NEt₃ (694 mg, 6.86 mmol) dropwise at rt. The resulting mixturewas stirred overnight at 85° C. and concentrated under reduced pressure.The residue was diluted with EA (50 mL) and washed with brine (40 mL).The organic layers were combined was dried over anhyd. Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with PE:EA (4:1) to affordt-butyl-N-(2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamateas a yellow solid (518 mg, 53%).

To a stirred solution oft-butyl-N-(2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate(450 mg, 0.837 mmol) in DCM (5 mL) was added TFA (2.50 mL) dropwise at0° C. The resulting mixture was stirred for 3 h at rt and concentratedunder reduced pressure. The residue was diluted with DCM (30 mL), washedwith NaHCO₃ (sat., aq., 40 mL), dried over anhyd. Na₂SO₄, the solidswere removed by filtration and the filtrate was concentrated underreduced pressure. The crude product was purified by preparative HPLC toafford6-amino-2-[3,5-dichloro-4-[(5-cyclobutyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneas a white solid (89.4 mg, 24%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.27 (s,1H), 12.15 (s, 1H), 7.85 (s, 2H), 7.46-7.47 (m, 1H), 6.52 (s, 2H),3.50-3.62 (m, 1H), 1.96-2.34 (m, 5H), 1.80-1.87 (m, 1H). LCMS (ESI, mz): 459 [M+Na]⁺.

Example 35. Synthesis of Compound 41

2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid was prepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid, with the exception that mixture was stirred for 2 h at 100° C. toafford a brown solid (200 mg, crude).

t-butyl-N-(2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamatewas prepared, from2-(3,5-dichloro-4-((3-isopropyl-1H-indol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid, similarly as described for t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate(from2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid) to afford a yellow solid (117 mg, crude).

6-amino-2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(compound 41) was prepared similarly as described for6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methylphenyl]-4H-1,2,4-triazine-3,5-dioneto afford a white solid (13 mg, 17%). ¹H NMR (300 MHz, MeOH-d₄) 7.88 (s,2H), 7.25-7.29 (m, 1H), 7.01 (s, 1H), 6.85-6.86 (m, 1H), 6.73-6.77 (m,1H), 2.98-3.08 (m, 1H), 1.28-1.36 (m, 6H).

Example 36. Synthesis of Compound 42

6-amino-2-(3,5-dichloro-4-((5-cyclopentyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewas prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneto afford a white solid (101 mg, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.21 (br, 1H), 12.17 (br, 1H), 7.85 (s,2H), 7.44 (s, 1H), 6.52 (br, 2H), 3.03-3.33 (m, 1H), 1.90-1.98 (m, 2H),1.50-1.78 (m, 6H). LCMS (ESI, m z): 451 [M+H]⁺.

Example 37. Synthesis of Compound 43

6-(4-amino-2,6-dimethylbenzyl)-2-phenylpyridin-3-ol was preparedsimilarly as described in WO 2010122980, and JP 2012106996.

6-amino-2-[4-[(5-hydroxy-6-phenylpyridin-2-yl)-methyl]-3,5-dimethylphenyl]-4H-1,2,4-triazine-3,5-dionewas prepared from 6-(4-amino-2,6-dimethylbenzyl)-2-phenylpyridin-3-olsimilarly as described in the conversion of6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one toprepare6-amino-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneto afford a white solid (43.8 mg, 49%). ¹H NMR (300 MHz, DMSO-d₆) δ9.32-9.89 (m, 2H), 7.99 (d, J=7.2 Hz, 2H), 7.31-7.43 (m, 3H), 7.19-7.24(m, 3H), 6.76 (d, J=8.1 Hz, 1H), 6.21 (s, 2H), 4.09 (s, 2H), 2.11 (s,6H). LCMS (ESI, m z): 416 [M+H]⁺.

Example 38. Synthesis of Compound 44

5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N-methyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamidewas prepared similarly as described for5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1-(4-methylbenzenesulfonyl)indole-3-carboxamideto afford a light brown solid (200 mg, 50%).

Subsequent tosyl group deprotection was performed similarly as describedfor the formation of5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N,N-dimethyl-1H-indole-3-carboxamideto afford5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-N-methyl-1H-indole-3-carboxamideas a yellow solid (21.5 mg, 14%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.85 (s,1H), 7.78 (s, 2H), 7.52 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H),6.91-6.94 (m, 1H), 2.87 (s, 3H). LCMS (ESI, m z): 471 [M+H]⁺.

Example 39. Synthesis of Compound 45

A 50 mL round-bottom flask was charged with5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole (1.00g, 2.10 mmol), NIS (0.71 g, 3.14 mmol), p-toluenesulfonic acid (0.05 g,0.314 mmol), DCM (30 mL). The reaction stirred for 5 h at rt and thenquenched with water (150 mL). The resulting mixture was extracted withDCM (3×200 mL) and the organic layers were combined, washed with brine(1×200 mL), dried over anhyd. Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified on a silica gel column withEA:PE (1:4) to provide5-(2,6-dichloro-4-nitrophenoxy)-3-iodo-1-(4-methylbenzenesulfonyl)indoleas a yellow solid (580 mg, 41%).

A 50 mL round-bottom was charged with5-(2,6-dichloro-4-nitrophenoxy)-3-iodo-1-(4-methylbenzenesulfonyl)indole(350 mg, 0.580 mmol),4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(155 mg, 0.696 mmol), PdCl₂(dppf) (42.5 mg, 0.058 mmol), K₂CO₃ (241 mg,1.74 mmol), ethylene glycol dimethyl ether (10 mL), and water (2 mL).The resulting solution stirred overnight under N₂ at 80° C. and wasquenched with water (10 mL), then extracted with EA (3×30 mL) and theorganic layers were combined, washed with brine (2×10 mL), dried overanhyd. Na₂SO₄, the solids were removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified on asilica gel column with EA:PE (1:4) to provide of5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzene-sulfonyl)-3-(3,3,3-trifluoroprop-1-en-2-yl)indoleas a white solid (220 mg, 53%).

A 100 mL round-bottom flask was charged with5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-3-(3,3,3-trifluoroprop-1-en-2-yl)indole(210 mg, 0.368 mmol), Pd/C (200 mg), and EA (20 mL) under hydrogen. Themixture was stirred for 3 h at rt. The reaction mixture was diluted withEA (60 mL) and filtered through celite, the celite pad was washed withEA (2×10 mL), the filtrate was concentrated under reduced pressure toafford the3,5-dichloro-4-[[1-(4-methylbenzene-sulfonyl)-3-(1,1,1-trifluoropropan-2-yl)indol-5-yl]oxy]anilineas a yellow solid (155 mg crude).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-3-(1,1,1-trifluoropropan-2-yl)-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,an orange solid (110 mg, 54%) was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-(1,1,1-trifluoropropan-2-yl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a yellow solid (80 mg, 54%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewith the exception that the reaction duration was 5 h.

Subsequent tosyl group deprotection via TBAF to afford2-(3,5-dichloro-4-[[3-(1,1,1-trifluoropropan-2-yl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a light-yellow solid (18.9 mg, 26%) was performed similarly asdescribed for2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile.¹H NMR (300 MHz, DMSO-d₆) δ 11.20 (br, 1H), 7.81 (s, 2H), 7.34-7.42 (m,2H), 7.04 (s, 1H), 6.69-6.72 (m, 1H), 3.92-3.97 (m, 1H), 1.46 (d, J=7.2Hz, 3H). LCMS (ESI, m z): 508[M−H]⁻.

Example 40. Synthesis of Compound 46

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (3.00 g, 9.29mmol) in DCM (25 mL) was added diethyl aluminum chloride (15 mL, 0.9 Min toluene, 13.5 mmol) dropwise at 0° C. The mixture was stirred at 0°C. for 30 min, then benzoyl chloride (1.96 g, 13.9 mmol) was added at 0°C. The reaction mixture was stirred at 0° C. for 3 h and quenched withwater (25 mL). The resulting mixture was extracted with DCM (3×20 mL).The organic layers were combined, washed with brine (3×20 mL), driedover anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified on a silica gel column with PE:EA (4:1) to afford3-benzoyl-5-(2,6-dichloro-4-nitro-phenoxy)-1H-indole as a light brownsolid (1.3 g, 26%).

To a solution of 3-benzoyl-5-(2,6-dichloro-4-nitrophenoxy)-1H-indole(1.3 g, 3.04 mmol) in THF (30 mL) was added LiAlH₄ (462 mg, 12.2 mmol)at 0° C. under N₂. The reaction mixture was stirred overnight at 60° C.and quenched with water (30 mL) at 0° C. To the resulting solution wasadded NaOH (1N, 30 mL) and followed by water (30 mL). The solids wereremoved by filtration, and the filter cake was washed with water (3×10mL). The filtrate was concentrated under reduced pressure. The residuewas purified by preparatory TLC with PE:EA (1:1) to afford4-[(3-benzyl-1H-indol-5-yl)oxy]-3,5-dichloroaniline as a light yellowsolid (250 mg, 21%).

Ethyl(2-(2-(4-((3-benzyl-1H-indol-5-yl)oxy)-3,5-dichlorophenyl)-hydrazineylidene)-2-cyanoacetyl)carbamate(300 mg, 52%) was prepared similarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)-phenyl)-hydrazineylidene)-acetyl)carbamate.

2-[4-[(3-benzyl-1H-indol-5-yl)oxy]-3,5-dichlorophenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a light brown solid was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethyl-phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewith the exception that the reaction duration was 5 h instead of 2 h(13.3 mg, 7%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.72 (s, 2H), 7.28 (d, J=9.0Hz, 1H), 7.10-7.23 (m, 5H), 7.03 (s, 1H), 6.77-6.80 (m, 1H), 6.54 (d,J=2.4 Hz, 1H), 3.98 (s, 2H). LCMS (ESI, m z): 502 [M−H]⁻.

Example 41. Synthesis of Compound 47

2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a yellow solid (120 mg, 32%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.77 (s, 2 h),7.33-7.37 (m, 1H), 7.24 (d, J=3.0 Hz, 1H), 6.80-6.84 (m, 2 h), 6.35-6.36(m, 1H). LCMS (ESI, m z): 412 [M−H]⁻.

Example 42. Synthesis of Compound 48

A 50 mL round-bottom was charged with5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (2.00 g, 6.19 mmol), DCM (10.0mL). SnCl₄(1.93 g, 7.42 mmol) was added at 0° C. The reaction mixturestirred at rt for 30 min. Propanoyl chloride (1.14 g, 12.3 mmol) wasadded, followed by CH₃NO₂ (15 mL). The reaction mixture was stirredovernight at rt and quenched with water (10 mL). The resulting mixturewas extracted with EA (3×200 mL) and the organic layers were combined,washed with brine (100 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on asilica gel column with EA:PE (9:1) to provide1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one as ayellow solid (1.6 g, 68.17%).

A 50 mL round-bottom flask was charged with1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one (1.90 g,5.01 mmol), THF (20 mL). NaH (0.802 g, 20.0 mmol, 60% in mineral oil)was added at 0° C. 4-toluene sulfonyl chloride (1.91 g, 10.0 mmol) wasadded at 0° C. The resulting solution was stirred at rt for 2 h andquenched with NaHCO₃ (sat. aq., 30 mL). The resulting mixture wasextracted with EA (3×80 mL) and the organic layers were combined, washedwith brine (2×40 mL), dried over anhyd. Na₂SO₄, the solids were removedby filtration and the filtrate was concentrated under reduced pressure.The crude was purified on a silica gel column with EA:PE (1:5) toprovide1-[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methyl-benzenesulfonyl)-indol-3-yl]propan-1-oneas a yellow solid (1.1 g, 41%).

NBH₄ (0.78 g, 20.6 mmol) was added to TFA (10 mL) at 0° C. under N₂.Then a solution of1-[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzene-sulfonyl)indol-3-yl]propan-1-one(1.10 g, 2.06 mmol) in DCM (30 mL) was added to the mixture. Thereaction mixture stirred overnight at rt and quenched with water (50mL), then extracted with DCM (3×150 mL) and the organic layers werecombined, washed with brine (1×100 mL), dried over anhyd. Na₂SO₄, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure to provide1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one as ayellow solid (1.1 g, 99%).

3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-propylindol-5-yl]-oxy]aniline,a yellow solid (870 mg, 74%) was prepared similarly as described for3,5-dichloro-4-[[3-isopropyl-1-(4-methy-lbenzenesulfonyl)-indol-5-yl]oxy]anilinewith the exception that the reaction stirred overnight at 50° C.

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-propyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,an orange solid (850 mg, 48%) was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-propylindol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a white solid (400 mg, 48%), was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewith the exception that the reaction duration was 5 h instead of 2 h.

Subsequent tosyl group deprotection via TBAF afford2-[3,5-dichloro-4-[(3-propyl-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas an orange solid (51.7 mg, 20%) was performed similarly as describedfor2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.80 (s, 2H), 7.30 (d, J=8.8Hz, 1H), 7.14 (s, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65-6.68 (m, 1H),2.52-2.57 (m, 2H), 1.54-1.64 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). LCMS (ESI,m z): 454 [M−H]⁻.

Example 43. Synthesis of Compound 49

To a stirred solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (2.00g, 6.19 mmol) in 1,2-dichloroethane (80 mL) was added InBr₃ (0.22 g,0.619 mmol) and isobutyryl chloride (0.99 g, 9.28 mmol) at 0° C. underN₂. The reaction mixture was stirred for 2 h at 85° C., then quenchedwith water (20 mL). The solution was extracted with EA (3×200 mL) andthe organic layers were combined, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified on asilica gel column with PE:EA (3:1) to afford1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]-2-methylpropan-1-oneas a light brown solid (1.5 g, 56%).

1-[5-(2,6-Dichloro-4-nitrophenoxy)-1-(4-methyl-benzenesulfonyl)-indol-3-yl]-2-methylpropan-1-one,a light yellow solid (1.3 g, 70%) was prepared similarly as describedfor1-[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methyl-benzenesulfonyl)-indol-3-yl]propan-1-one.

5-(2,6-Dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-3-(2-methylpropyl)indole,a light brown solid (1.2 g, 85%), was prepared similarly as describedfor 1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one withthe exception that, after quenching with water, the reaction wasneutralized by the addition of NaOH solution at 0° C.

3,5-Dichloro-4-[[1-(4-methyl-benzenesulfonyl)-3-(2-methylpropyl)indol-5-yl]oxy]anilineas a light yellow solid (1.2 g, 95%) was prepared similarly as describedfor3,5-dichloro-4-[[3-isopropyl-1-(4-methy-lbenzenesulfonyl)-indol-5-yl]oxy]aniline.

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-isobutyl-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,a red solid (860 mg, 48%), was prepared similarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-Dichloro-4-[[1-(4-methylbenzenesulfonyl)-3-(2-methylpropyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a red solid (600 mg, 56%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Tosyl group deprotection to afford2-(3,5-dichloro-4-[[3-(2-methylpropyl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas an orange solid (51.2 mg, 22%) was prepared similarly as describedfor2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (300 MHz, MeOH-d₄) δ 7.78 (s, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.02(s, 1H), 6.73-6.83 (m, 2H), 2.51 (d, J=7.2 Hz, 2H), 1.83-1.92 (m, 1H),0.90-1.00 (m, 6H). LC-MS (ESI, m z): 468 [M−H].

Example 44. Synthesis of Compound 50

To a solution of 5-(2,6-dichloro-4-nitrophenoxy)-1H-indole (2.00 g, 6.19mmol) in DCM (50 mL) was added SnCl₄ (1.93 g, 7.43 mmol) at 0° C. Thesolution warmed to rt and stirred for 30 min, then cyclopropanecarbonylchloride (0.78 g, 7.43 mmol) was added in small portions to thesuspension by syringe, followed by nitromethane (40 mL). The reactionmixture was stirred at rt for 2 h, after which ice water (40 mL) wasslowly added. The solids were removed by filtration, and the filtratewas extracted with EA (3×50 mL), the organic layers were combined, driedover anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified on a silica gel column with hexane:EA (3:1) to afford3-cyclopropanecarbonyl-5-(2,6-dichloro-4-nitrophenoxy)-1H-indole as ayellow solid (1.3 g, 48%).

3-Cyclopropanecarbonyl-5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)-indole,a light brown solid (1.8 g, 70%) was prepared similarly as described for1-[5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methyl-benzenesulfonyl)-indol-3-yl]propan-1-one.

3-(Cyclopropylmethyl)-5-(2,6-dichloro-4-nitrophenoxy)-1-(4-methylbenzenesulfonyl)indole,a light brown solid (1.6 g, 77%) was prepared similarly as described for1-[5-(2,6-dichloro-4-nitrophenoxy)-1H-indol-3-yl]propan-1-one with theexception that, after quenching with water, the reaction was neutralizedby the addition of NaOH solution at 0° C.

3,5-Dichloro-4-[[3-(cyclopropylmethyl)-1-(4-methylbenzenesulfonyl)-indol-5-yl]oxy]aniline,a light yellow solid (1.3 g, 78%) was prepared similarly as describedfor3,5-dichloro-4-[[3-isopropyl-1-(4-methy-lbenzenesulfonyl)-indol-5-yl]oxy]aniline.

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-(cyclopropylmethyl)-1-tosyl-1H-indol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,a red solid (1.18 g, 62%) was prepared similarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-Dichloro-4-[[3-(cyclopropylmethyl)-1-(4-methylbenzenesulfonyl)indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a light brown solid (732 mg, 62%), purified via reverse phasechromatography using a C18 column, was prepared similarly as describedfor2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Tosyl group deprotection to afford2-(3,5-dichloro-4-[[3-(cyclopropylmethyl)-1H-indol-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a orange solid (121 mg, 22%) was prepared similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (300 MHz, MeOH-d₄) δ 7.79 (s, 2H), 7.28-7.31 (m, 1H), 7.11 (s,1H), 6.77-6.85 (m, 2H), 2.57 (d, J=6.6 Hz, 2H), 0.95-1.02 (m, 1H),0.47-0.50 (m, 2H), 0.13-0.16 (m, 2H). LCMS (ESI, m z): 466 [M−H].

Example 45. Synthesis of Compound 51

To a stirred solution of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (14.0 g, 70.7mmol), Cs₂CO₃ (34.7 g, 106 mmol) in DMF (200 mL) was added[2-(chloro-methoxy)ethyl]trimethylsilane (17.7 g, 106 mmol) dropwise at0° C. The mixture was stirred for 2 h at rt and quenched with water (400mL). The mixture was extracted with EA (3×500 mL) and the organic layerswere combined, dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with PE:EA(18:1) to afford 2-bromo-5-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazine as a yellow solid (21 g, 86%).

To a stirred solution of2-bromo-5-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-b]pyrazine(20.0 g, 60.9 mmol) and 4-amino-2,6-dichloro-phenol (16.3 g, 91.4 mmol)in DMSO (200 mL) were added K₂CO₃ (25.3 g, 183 mmol) and CuI (4.64 g,24.4 mmol) at rt. The mixture was stirred for overnight at 90° C. underN₂. The reaction was quenched with sat. NH₄C₁ (aq.) and extracted withEA (3×800 mL). The organic layers were combined, washed with brine(2×600 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse phase column chromatography using a C₁₈column (ACN:H₂O=10-60% in 50 min) to afford3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]anilineas a yellow solid (2.2 g, 8%).

To a stirred solution of3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy]-methyl]-pyrrolo[2,3-b]pyrazin-2-yl)oxy]aniline(2.20 g, 5.17 mmol) in CH₃CN (30 mL) was added(dimethoxymethyl)dimethylamine (1.54 g, 12.9 mmol) dropwise at rt. Themixture was stirred for overnight at 80° C., quenched with water (50mL), then was extracted with EA (3×50 mL) and the organic layers werecombined, washed with brine (2×40 mL), dried over anhyd. Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with PE:EA (1:1) to affordN-[3,5-dichloro-4-[(5-[[2-(trimethyl-silyl)ethoxy]methyl]pyrrolo-[2,3-b]pyrazin-2-yl)oxy]phenyl]-N,N-dimethylmethanimid-amideas a brown oil (1.875 g, 72%).

To a stirred solution ofN-[3,5-dichloro-4-[(5-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]phenyl]-N,N-dimethylmethanimidamide(1.83 g, 3.81 mmol) in DCM (20 mL) was added NIS (1.11 g, 4.95 mmol) andp-toluenesulfonic acid (0.20 g, 1.16 mmol) in portions at 0° C. Thereaction mixture was stirred for 4 h at rt and quenched with water (50mL). The mixture was extracted with DCM (3×50 mL) and the organic layerswere combined, washed with brine (2×40 mL), dried over anhyd. Na₂SO₄,the solids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with PE:EA (4:1) to affordN-[3,5-dichloro-4-[(7-iodo-5-[[2-(trimethylsilyl)ethoxy]methyl]-pyrrolo[2,3-b]pyrazin-2-yl)oxy]phenyl]-N,N-dimethylmethanimidamideas a brown oil (1.33 g, 55%).

To a stirred mixture ofN-[3,5-dichloro-4-[(7-iodo-5-[[2-(trimethylsilyl)-ethoxy]methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]phenyl]-N,N-dimethyl-methanimidamide(980 mg, 1.62 mmol), PdCl₂(dppf) (106 mg, 0.162 mmol) and K₂PO₃ (515 mg,2.42 mmol) in dioxane (33 mL) and water (6 mL) were added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.09 g, 6.47mmol) at rt. The mixture was stirred for overnight at 55° C. under N₂,then quenched with water (60 mL). The mixture was extracted with EA(3×60 mL) and the organic layers were combined, washed with brine (3×50mL), dried over anhyd. Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith PE:EA (7:1) to affordN-(3,5-dichloro-4-[[7-(prop-1-en-2-yl)-5-[[2-(trimethylsilyl)ethoxy]methyl]-pyrrolo[2,3-b]pyra-zin-2-yl]oxy]-phenyl)-N,N-dimethylmethanimidamideas a yellow solid (688 mg, 81%).

To a stirred mixture of2-(3,5-dichloro-4-[[3-(prop-1-en-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(688 mg, 1.51 mmol) in EA (24.0 mL) was added Pd/C (90.0 mg, 0.846 mmol)at rt under N₂. The mixture was stirred for 1 h at rt under H₂, thesolids were removed by filtration through celite, and the filtrate wasconcentrated under reduced pressure to provide2-[3,5-dichloro-4-([3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow oil (670 mg, 93%). The crude product was used in the nextstep without further purification.

To a stirred solution of(E)-N-[3,5-dichloro-4-[(7-isopropyl-5-[[2-(trimethyl-silyl)ethoxy]methyl]pyrrolo[2,3-b]pyrazin-2-yl)oxy]phenyl]-N,N-dimethyl-methanimid-amide(670 mg, 1.28 mmol) in ethyl alcohol (15 mL) was added ethylenediamine(347 mg, 5.77 mmol) dropwise at rt. The mixture was stirred overnight at80° C. then concentrated under reduced pressure. The mixture was dilutedwith EA (40 mL), washed with brine (2×30 mL), dried over anhyd. Na₂SO₄,the solids were removed by filtration and the filtrate was concentratedunder reduced pressure to afford3,5-dichloro-4-[(7-isopropyl-5-[[2-(trimethylsilyl)-ethoxy]methyl]-pyrrolo[2,3-b]-pyrazin-2-yl)oxy]aniline as a brown solid (700 mg, crude).

Ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((7-isopropyl-5-((2-(trimethyl-silyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)oxy)phenyl)hydrazineylidene)-acetyl)carbamate,a red solid (800 mg, crude) was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineyl-idene)-acetyl)carbamate.

2-[3,5-dichloro-4-[(7-isopropyl-5-[[2-(trimethylsilyl)ethoxy]methyl]-pyrrolo[2,3-b]pyrazin-2-yl)-oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a brown solid (186 mg, 21%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Tosyl group deprotection to afford2-[3,5-dichloro-4-([7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a white solid (25.5 mg, 17%) was prepared similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (300 MHz, DMSO-d₆) δ 12.45 (br, 1H), 12.21 (s, 1H), 8.10 (s, 2H),7.43 (s, 1H), 3.58 (s, 3H), 3.11-2.97 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).LCMS (ESI, m z): 456 [M−H]⁺.

Example 46. Synthesis of Compound 52

To a stirred solution of 3-chloro-7H-pyrrolo[2,3-c]pyridazine (4.00 g,26.1 mmol) and NEt₃ (3.96 g, 39.2 mmol) in DCM (50 mL) was added[2-(chloromethoxy)ethyl]trimethylsilane (13.02 g, 78.4 mmol) dropwise at0° C. The mixture was stirred for overnight at rt and quenched withwater (100 mL), then was extracted with DCM (3×150 mL). The combinedorganic layers were washed with brine (2×100 mL), dried over anhyd.Na₂SO₄, filtrated and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography, eluted with PE:EA(10:1) to afford3-chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyrid-azineas a yellow solid (3.50 g, 47%).

To a stirred solution of3-chloro-7-[[2-(trimethylsilyl)ethoxy]methyl]-pyrrolo[2,3-c]pyridazine(3.20 g, 11.3 mmol) and(E)-N′-(3,5-dichloro-4-hydroxyphenyl)-N,N-dimethylformimidamide (2.63 g,11.3 mmol) in THF (40 mL) was added Pd₂(dba)₃-chloroform adduct (1.17 g,1.13 mmol), JosiPhos (625 mg, 1.13 mmol) and Cs₂CO₃ (7.35 g, 22.5 mmol)at rt. The mixture was stirred for 48 h at 95° C. under N₂ and quenchedwith water (50 mL). The mixture was extracted with EA (3×60 mL). Thecombined organic layers were washed with brine (2×50 mL), dried overanhyd. Na₂SO₄, filtrated and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted withPE:EA (1:2) to afford(E)-N′-(3,5-dichloro-4-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamideas a yellow solid (2.2 g crude).

To a stirred mixture of(E)-N-[3,5-dichloro-4-[(7-[[2-(trimethylsilyl)-ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-N,N-dimethylmethanimidamide(1.12 g, 2.33 mmol) in DCM (12 mL) was added NIS (0.68 g, 3.02 mmol) andp-toluenesulfonic acid (0.12 g, 0.699 mmol) in portions at 0° C. Themixture was stirred for 4 h at rt and quenched with water (30 mL) at rt.The mixture was extracted with DCM (3×40 mL). The combined organiclayers were washed with brine (2×30 mL), dried over anhyd. Na₂SO₄ thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with PE:EA (4:1) to afford(E)-N-[3,5-dichloro-4-[(5-iodo-7-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-N,N-dimethyl-methanimidamide as a brown solid (600 mg, crude).

To a stirred mixture of(E)-N-[3,5-dichloro-4-[(5-iodo-7-[[2-(trimethylsilyl)-ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-N,N-dimethylmethanimidamide(650 mg, 1.07 mmol), 1,1′-Bis (di-t-butylphosphino)ferrocene palladiumdichloride (69.9 mg, 0.107 mmol) and K₂PO₃ (341 mg, 1.61 mmol) in1,4-dioxane (10 mL) and water (2 mL) was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (721 mg, 4.29mmol) at rt. The mixture was stirred for 4 h at 50° C. under N₂ andquenched with water (50 mL) at rt, then was extracted with EA (3×50 mL).The combined organic layers were washed with brine (2×40 mL), dried overanhyd. Na₂SO₄, the solids were removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with PE:EA (3:1) to afford(E)-N-(3,5-dichloro-4-[[5-(prop-1-en-2-yl)-7-[[2-(trimethylsilyl)ethoxy]-methyl]pyrrolo[2,3-c]pyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamideas a brown solid (675 mg, crude).

To a stirred mixture of(E)-N-(3,5-dichloro-4-[[5-(prop-1-en-2-yl)-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl]oxy]phenyl)-N,N-dimethyl-methanimidamide(800 mg, 1.54 mmol) in EA (10 mL) was added Pd:C (300 mg) at rt underhydrogen. The mixture was stirred for 1 h at rt, then was filtered andthe filter cake was washed with EA (3×20 mL). The combined organiclayers were concentrated under reduced pressure to afford(E)-N-[3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-N,N-dimethyl-methanimidamideas a yellow oil (1 g, crude).

To a stirred solution of(E)-N-[3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-N,N-dimethyl-methanimidamide(1.00 g, 1.92 mmol) in EtOH (9 mL) was added NaOH (9 mL, 9.00 mmol, 1 M)dropwise at rt. The mixture was stirred for 3 h at 80° C. then dilutedwith water (30 mL) and extracted with EA (3×40 mL). The combined organiclayers were washed with brine (2×30 mL), filtrated and concentratedunder reduced pressure to afford3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)-ethoxy]methyl]-pyrrolo[2,3-c]pyridazin-3-yl)oxy]anilineas a brown oil (900 mg, crude).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-7-((2-(trimethylsilyl)-ethoxy)methyl)-7H-pyrrolo[2,3-c]pyridazin-3-yl)oxy)phenyl)hydrazineylidene)-acetyl)carbamate,a red solid (920 mg) was prepared similarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate with the exception that the reaction stirred for 10 min at OC.The crude product was used in the next step without furtherpurification.

2-[3,5-dichloro-4-[(5-isopropyl-7-[[2-(trimethylsilyl)-ethoxy]methyl]pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile as a brown solid (690mg, 69%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Tosyl group deprotection to afford2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid (24.8 mg, 31%) was prepared similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) 13.28 (s, 1H), 12.03-12.05 (m, 1H), 7.83 (s,1H), 7.79 (s, 2H), 7.73-7.75 (m, 1H), 3.12-3.19 (m, 1H), 1.32 (d, J=6.8Hz, 6H). LCMS (ESI, m z): 458[M+H]⁺.

Example 47. Synthesis of Compound 53

The conversion of compound 52 to 53 was analogous to the method toprepare6-amino-2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-phenyl]-4H-1,2,4-tri-azine-3,5-dioneto afford2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid as a yellow solid (190 mg). The crude product was used in the nextstep without further purification.

To a stirred solution of2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (150 mg, 0.314 mmol) and DPPA (260 mg, 0.943 mmol) in tBuOH (3 mL)was added NEt₃ (127 mg, 1.26 mmol) dropwise at rt. The resulting mixturewas stirred overnight at 85° C. then quenched with water (30 mL) at rtand extracted with EA (3×30 mL). The combined organic layers were washedwith brine (2×20 mL), dried over anhyd. Na₂SO₄, the solids were removedby filtration and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith PE:EA (3:1) to affordt-butyl-N-[2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]-oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamateas a yellow solid (130 mg, crude).

To a stirred solution oft-butyl-N-[2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(120 mg) in DCM (1 mL) was added TFA (2 mL) dropwise at rt. Theresulting mixture was stirred for 2 h at rt and concentrated underreduced pressure. The reaction was quenched with sat aq. Na₂CO₃ (20 mL)at rt. The resulting mixture was extracted with DCM (3×30 mL). Thecombined organic layers were washed with brine (2×20 mL), dried overanhyd. Na₂SO₄, filtrated and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to afford6-amino-2-[3,5-dichloro-4-([5-isopropyl-7H-pyrrolo[2,3-c]pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dioneas a white solid (44.8 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 11.41-12.07 (br,2H), 7.85-7.92 (m, 2H), 7.68-7.79 (m, 2H), 6.41 (s, 2H), 3.10-3.20 (m,1H), 1.36-1.21 (m, 6H).

LCMS (ESI, m z): 448[M+H]⁺.

Example 48. Synthesis of Compound 54

To a mixture of[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (50 mg, 86.1 μmol),2H-1,2,4-triazine-3,5-dione (29.2 mg, 258 μmol),di-t-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triiso-propylphenyl)phenyl]phosphane(8.28 mg, 17.2 μmol) and K₂CO₃ (35.7 mg, 258 μmol) in t-BuOH (3 mL) wasadded Pd₂(dba)₃ (7.89 mg, 8.61 μmol) under N₂ protection. The mixturewas stirred at 110° C. for 90 min under microwave irradiation. Thereaction was diluted with H₂O (5 mL) and extracted with EA (3×5 mL). Thecombined organic layers were washed with brine (5 mL), dried over anhyd.Na₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated to give a residue, which was purified by silica gelchromatography (0˜50% EA in PE) to give2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dioneas a yellow solid (60 mg, 98%, 37% purity).

Tosyl group deprotection was performed similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileto afford2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dioneas a white solid (5.88 mg, 15%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.81 (brs, 1H), 8.23 (br s, 1H), 7.59 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.29 (s,1H), 7.16 (s, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.23 (s, 2H), 3.20 (td,J=6.8, 13.6 Hz, 1H), 2.38 (s, 6H), 1.33 (d, J=6.9 Hz, 6H). LCMS (ESI, mz): 390.3[M+H]⁺.

Example 49. Synthesis of Compound 55

5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolyl-sulfonyl)pyrrolo[3,2-b]pyridine,a yellow solid (1.36 g, 73%) was prepared similarly as described for5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine.

4-[[3-isopropyl-1-(p-tolylsulfon-yl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol,a white solid (1 g, 88%) was prepared similarly as described for4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenol.

A mixture of[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (600 mg, 1.03 mmol), bis(pinacolato)diboron(525 mg, 2.07 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (84.4 mg, 103 μmol), KOAc (304mg, 3.10 mmol) in DMSO (10 mL) was degassed and purged with N₂. Themixture was stirred at 130° C. for 16 h under N₂. The reaction mixturewas partitioned between H₂O (30 mL) and EA (50 mL). The organic phasewas separated, washed with brine (30 mL), dried over Na₂SO₄, the solidswere removed by filtration and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography (0˜10% EA in PE) to give5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridineas a yellow solid (340 mg, 59%).

To a solution of5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine(290 mg, 519 μmol) in acetone (12 mL) and H₂O (6 mL) was added NaIO₄(1.11 g, 5.19 mmol, 287.71 μL) and NH₄OAc (400 mg, 5.19 mmol) at 25° C.After the addition, the mixture was stirred at 25° C. for 16 h. Thereaction mixture was extracted with EA (3×10 mL). The organic layerswere washed with brine (20 mL), dried over Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure, then purified by preparatory TLC (SiO₂, PE:EA=1:1) to give[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-boronic acid as a white solid (190 mg,76%).

A mixture of 6-amino-4-(benzyloxymethyl)-2H-1,2,4-triazine-3,5-dione(252 mg, 1.02 mmol),[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]boronicacid (440 mg, 923 μmol), pyridine (146 mg, 1.85 mmol, 149 μL), 4 Åmolecular sieves (5 g) and Cu(OAc)₂ (83.9 mg, 462 μmol) in DMF (15 mL)was degassed and purged with O₂, then the mixture was stirred at 60° C.for 16 h under an 02 atmosphere (via balloon). The reaction mixture wascooled to 25° C. and diluted with EA (30 mL), then the solids wereremoved by filtration. The filtrate was washed with H₂O (3×10 mL), brine(20 mL), dried over Na₂SO₄, the solids were removed by filtration andthe filtrate was concentrated under reduced pressure to give a residue.The residue was purified by silica gel chromatography (0˜30% EA in PE)to give6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyrid-ine-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dioneas a yellow gum (140 mg, 20%).

A solution of6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolyl-sulfonyl)pyrrolo[3,2-b]pyridine-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(140 mg, 206 μmol) in TFA (5 mL) was stirred at 80° C. for 16 hr. Thereaction mixture was diluted with EA (10 mL), and the pH was adjusted to7 by NaHCO₃ (sat. aq.). The organic layer was separated, and the aq.layer was extracted with EA (3×20 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure togive a residue, which was purified by preparatory TLC (SiO₂, PE:EA=1:2)to give6-amino-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)-pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dioneas a white solid (45 mg, 39%).

Tosyl group deprotection to afford6-amino-2-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione,a white solid (11.3 mg, 35%) was prepared similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ=12.07 (br s, 1H), 10.80 (br s, 1H), 7.55 (d,J=8.4 Hz, 1H), 7.29 (s, 1H), 7.19 (s, 2H), 6.63 (d, J=8.4 Hz, 1H), 6.29(s, 2H), 4.21 (s, 2H), 3.25-3.19 (m, 1H), 2.34 (s, 6H), 1.34 (d, J=6.9Hz, 6H). LCMS (ESI, m z): 405.6 [M+H]⁺.

Example 50. Synthesis of Compound 56

2-(2,6-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-7-isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyraz-ine,a yellow solid (520 mg, 73%), was prepared similarly as described for5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridinewith the exception that the reaction was heated for 12 h.

(4-((7-Isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-3,5-dimethylphenyl)boronicacid, a yellow solid (670 mg, crude) was prepared similarly as describedfor[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-boronicacid.

4-((Benzyloxy)methyl)-2-(4-((7-isopropyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione,a light yellow solid (110 mg, 11%), was prepared similarly as describedfor6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyrid-ine-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione.

Tosyl group deprotection to give2-(4-((7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione,a white solid (20 mg, 80%), was prepared similarly as described for2-[3,5-dichloro-4-(1H-indol-5-yloxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ=12.48 (brs, 1H), 11.54 (br s, 1H), 7.93 (s,1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.16 (s, 2H), 4.26 (s, 2H), 3.09-3.17(m, 1H), 2.40 (s, 6H), 1.31 (d, J=6.8 Hz, 6H). LCMS (ESI, m z):391.6[M+H]⁺.

Example 51. Synthesis of Compound 57

2,2,2-Trifluoro-N-(4-(hydroxy(3-isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide,a white solid (294 mg, 36%), was prepared similarly as described for2,2,2-trifluoro-N-(4-(hydroxy(3-pentyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamidewith the exception that t-butyl lithium was used (2.2 eq).

2,2,2-Trifluoro-N-(4-((3-isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)acetamide(209 mg, 81%), a white solid, was prepared similarly as described for2,2,2-trifluoro-N-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]methyl]-3,5-dimethylphenyl)acetamide.

Trifluoroacetamide deprotection to afford4-((3-isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylaniline (141 mg,96%) was prepared similarly as described for3,5-dimethyl-4-((3-pentyl-1H-indazol-5-yl)methyl)aniline.

2-(4-((3-Isopropyl-1H-indazol-5-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,an orange solid (10 mg, 8%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.¹H NMR (DMSO-d₆ 400 MHz): 1.31 (d, J=6.8 Hz, 6H); 2.28 (s, 6H);3.22-3.27 (m, 1H); 4.15 (s, 2H), 6.96 (d, J=8.3 Hz, 1H); 7.18 (s, 2H);7.35 (d, J=8.3 Hz, 1H); 7.38 (s, 1H); 12.47 (s, 1H); 12.99 (s, 1H).

Example 52. Synthesis of Compound 58

6-Amino-2-[3,5-dichloro-4-[(5-cyclohexyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dionewas prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneto afford a white solid (101.1 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) 12.18(br, 2H), 7.83 (s, 2H), 7.35-7.36 (m, 1H), 6.47 (s, 2H), 2.68-2.72 (m,1H), 1.21-1.84 (m, 10H). LCMS (ESI, m z): 465 [M+H]⁺.

Example 53. Synthesis of Compound 59

3,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridazine was preparedsimilarly as described for 3,6-dichloro-4-isopropylpyridazine (see alsoSamaritoni, J. G. Homolytic alkylation of 3,6-dichloropyridazine. Org.Prep. Proced. Int. 1988, 20, 117-121) as a white solid (5.3 g, 68%).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazineylidene)-acetyl)carbamate,a brown solid (42 g, crude) was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineyl-idene)-acetyl)carbamate with the exception that the reaction was stirred for 10 min at0° C.

To a stirred mixture of ethyl(2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazineylidene)acetyl)carbamate(41.0 g, 119 mmol) in DMA (400 mL) was added KOAc (46.6 g, 475 mmol) inportions at rt. The resulting mixture was stirred for 2 h at 110° C. andquenched with water (400 mL). The resulting mixture was extracted withEA (3×600 mL) and the organic layers were combined, washed with brine(3×400 mL), dried over anhyd. Na₂SO₄ the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with DCM:MeOH(19:1) to afford2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid (24.3 g, 62%).

To a stirred solution of2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(20 g, 66.9 mmol) in AcOH (200 mL) was added HCl (100 mL) at rt. Theresulting mixture was stirred for 5 h at 110° C. and concentrated underreduced pressure. The residue was adjusted to pH=9 with NaOH (1 M). Theresulting mixture was extracted with EA (2×80 mL). The mixture wasadjusted to pH=5 with HCl (1 M), then extracted with EA (3×100 mL) andthe organic layers were combined, washed with brine (2×60 mL), driedover anhyd. Na₂SO₄ and concentrated under reduced pressure to afford2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid as a yellow solid (19 g, crude).

To a stirred solution of2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (13.8 g, 43.4 mmol) in tBuOH (150 mL) was added DPPA (29.9 g, 108mmol) and NEt₃ (17.7 g, 174 mmol) at rt. The mixture was stirred forovernight at 85° C. and concentrated under reduced pressure, dilutedwith water (100 mL) and extracted with EA (3×120 mL). The combinedorganic layers were washed with brine (2×80 mL), dried over anhyd.Na₂SO₄, filtrated and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with DCM:MeOH (40:1) toaffordt-butyl-N-(2-[3,5-dichloro-4-[(diphenoxyphosphoryl)-oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbam-ateas a yellow solid (16.0 g, 53%).

To a stirred mixture oft-butyl-N-(2-[3,5-dichloro-4-[(diphenoxyphosphor-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate(11.0 g, 17.7 mmol) in tBuOH (200 mL) was added NaOH (25 mL, 2 M)dropwise at rt. The resulting mixture was stirred for 4 h at rt andconcentrated under reduced pressure. The mixture was diluted with water(50 mL), acidified to pH 6 with HCl (1 M), and extracted with EA (3×100mL). The organic layers were combined, washed with brine (2×70 mL),dried over anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with PE:EA (1:1) to affordt-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]-carbam-ateas a yellow solid (6.0 g, 78%).

To a stirred mixture of 3,6-dichloro-4-(oxan-4-yl)pyridazine (300 mg,1.29 mmol) andt-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(501 mg, 1.29 mmol) in DMSO (10 mL) was added K₂CO₃ (534 mg, 3.86 mmol)and CuI (123 mg, 0.644 mmol) at rt. The mixture was stirred for 16 h at110° C. under N₂ and quenched with water (30 mL) at rt. The mixture wasextracted with EA (3×40 mL) and the organic layers were combined, washedwith brine (2×30 mL), dried over anhyd. Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography DCM:MeOH (3:1) to afford6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxan-4-yl)pyrida-zin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a brown solid (280 mg, 36%).

To a stirred mixture of6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxan-4-yl)-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(250 mg, 0.515 mmol) in AcOH (4 mL) was added NaOAc (169 mg, 2.06 mmol)at rt. The mixture was stirred for overnight at 100° C. then quenchedwith water (30 mL). The mixture was extracted with EA (3×30 mL), theorganic layers were combined, washed with brine (2×30 mL), dried overanhyd. Na₂SO₄, the solids were removed by filtration and the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with DCM:MeOH (20:1) to afford crudeproduct that was purified by preparative HPLC to afford6-amino-2-(3,5-dichloro-4-[[5-(oxan-4-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (23.3 mg, 10%). ¹H NMR (300 MHz, DMSO-d₆) 12.26-12.28(m, 2H), 7.86 (s, 2H), 7.44-7.46 (m, 1H), 6.54 (s, 2H), 3.93-3.99 (m,2H), 3.41-3.49 (m, 2H), 2.95-3.05 (m, 1H), 1.58-1.78 (m, 4H). LCMS (ESI,m z): 467 [M+H]⁺.

Example 54. Synthesis of Compounds 60 and 60-A

To a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (10.0 g,48.4 mmol) in THF (100 mL) was added NaOCH₃ (9.57 g, 53.1 mmol, 30% inMeOH) dropwise at 0° C. The mixture was stirred for 0.5 h at 0° C. thenquenched with NH₄Cl (sat., aq., 150 mL). The mixture was extracted withEA (3×150 mL), the organic layers were combined, washed with brine(2×150 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thesample was purified by column chromatography (EA:PE=0-30% over 30 min)to afford methyl 6-chloro-3-methoxy-pyridazine-4-carboxylate as a yellowsolid (7.3 g, 60%).

A mixture of methyl 6-chloro-3-methoxypyridazine-4-carboxylate (9.00 g,44.4 mmol) in THF (100 mL) was added dropwise CH₃MgBr (59.2 mL, 178mmol, 3 M in Et₂₀) at −50° C. The mixture was stirred for 2 h at −50° C.to 0° C., then quenched with sat. aq. NH₄C₁ (150 mL) and extracted withEA (3×150 mL). The organic layers were combined, washed with brine(2×150 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure toafford crude product that was purified by silica column chromatography(EA:PE=0˜30% over 20 min) to afford2-(6-chloro-3-methoxypyridazin-4-yl)propan-2-ol as an off-white solid(2.35 g, 25%).

To a mixture of 2-(6-chloro-3-methoxypyridazin-4-yl)propan-2-ol (2.90 g,14.3 mmol),(E)-N′-(3,5-dichloro-4-hydroxyphenyl)-N,N-dimethylmethan-imidamide (3.67g, 15.7 mmol), Cs₂CO₃ (9.33 g, 28.6 mmol) and JosiPhos (0.85 g, 1.43mmol) in THF (30 mL) was added Pd₂(dba)₃-CHCl₃ (1.48 g, 1.43 mmol). Themixture was stirred for 48 h at 95° C. under N₂ then quenched with water(50 mL). The mixture was extracted with EA (3×80 mL) and the organiclayers were combined, washed with brine (2×50 mL), dried over anhyd.Na₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The sample was purified by columnchromatography and eluted with EA:PE to afford(E)-N′-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-methoxypyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamideas a yellow solid (690 mg, 11%).

To a mixture of(E)-N′-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-meth-oxypyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(690 mg, 1.73 mmol) and KI (861 mg, 5.18 mmol) in DCM (10 mL) was addedTMSCl (563 mg, 5.18 mmol) at 0° C. The mixture was stirred overnight atrt and quenched with water (20 mL). The mixture was extracted with DCM(3×30 mL) and the organic layers were combined, washed with brine (2×20mL), dried over anhyd. Na₂SO₄, the solids were removed by filtration andthe filtrate was concentrated under reduced pressure to provide(E)-N′-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamideas a yellow solid (670 mg, crude).

A mixture of(E)-N′-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(670 mg, 1.74 mmol) in ethanol (10 mL) and NaOH (10 mL, 1 M). Themixture was stirred overnight at 70° C. then concentrated under reducedpressure, diluted with water (50 mL) and extracted with EA (3×50 mL).The organic layers were combined, washed with brine (2×30 mL), driedover anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to provide6-(4-amino-2,6-dichlorophenoxy)-4-(2-hydroxypropan-2-yl)-2H-pyridazin-3-oneas a yellow solid (560 mg, 83%).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-(2-hydroxypropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,a yellow solid (500 mg, 55%), was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]-phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrileas a yellow solid (380 mg, 80%) was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

Further steps in the synthesis of compound 60,6-amino-2-(3,5-dichloro-4-[[5-(2-hydroxypropan-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (63.9 mg, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm:12.2-12.4 (m, 2H), 7.87 (s, 2H), 7.53 (s, 1H), 6.53 (s, 2H), 5.50 (s,1H), 1.51 (s, 6H). LCMS (ESI, m z): 441 [M+H]⁺.

Compound 60-A,6-amino-2-(3,5-dichloro-4-[[6-oxo-5-(prop-1-en-2-yl)-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dionewas obtained as a white solid (13.8 mg, 8%). ¹H NMR (300 MHz, DMSO-d₆) δppm: 12.0-12.5 (m, 2H), 7.87 (s, 2H), 7.54 (s, 1H), 6.49 (s, 3H), 5.57(s, 1H), 2.12 (s, 3H). LCMS (ESI, m z): 423 [M+H]⁺.

Example 55. Synthesis of Compound 61

To a solution of diisopropylamine (5.18 g, 51.2 mmol) in THF (60 mL) wasadded dropwise n-buLi (19.5 mL, 2.5 M in hexane, 48.7 mmol) at −78° C.under N₂. The solution was stirred at −78˜−50° C. for 0.5 h. Methyl2-(3,3-difluoro-cyclobutyl)acetate (prepared according to proceduresdetailed in WO2015005901 and WO20150023913) (4 g, 24.4 mmol) in THF (10mL) was added dropwise at −78° C. The solution was stirred at −78° C.for 0.5 h. CH₃I (4.50 g, 31.7 mmol) was added at −78° C. The reactionmixture was slowly warmed to rt over 3 h, then quenched with water (30mL) and extracted with EA (3×50 mL). The organic layer was dried overanhyd. Na₂SO₄, the solids were removed by filtration and the filtratewas concentrated under reduced pressure to provide methyl2-(3,3-difluorocyclobutyl)propanoate as a yellow oil (3.9 g, crude).

To a solution of methyl 2-(3,3-difluorocyclobutyl)propanoate (3.8 g,21.3 mmol) in THF (40 mL) and MeOH (10 mL) was added NaOH solution (10N, 20 mL). The solution was stirred overnight at rt. The pH was adjustedto 5 with HCl (1 N). The mixture was extracted with EA (3×50 mL). Theorganic phases were combined, washed with brine, dried over anhyd.Na₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure to provide2-(3,3-difluorocyclobutyl)propanoic acid as a yellow oil (1.5 g, crude).

3,6-Dichloro-4-[1-(3,3-difluoro-cyclobutyl)ethyl]-pyridazine wasprepared similarly as described for 3,6-dichloro-4-isopropylpyridazine(see also Samaritoni, J. G. Homolytic alkylation of3,6-dichloropyridazine. Org. Prep. Proced. Int. 1988, 20, 117-121) toafford a yellow oil (390 mg, 21%).

6-Amino-2-[3,5-dichloro-4-([6-chloro-5-[1-(3,3-difluorocyclobutyl)-ethyl]pyrida-zin-3-yl]oxy)-phenyl]-4H-1,2,4-triazine-3,5-dione,a yellow oil (280 mg, 33%) was prepared similarly as described for6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxan-4-yl)pyrida-zin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione.

To a solution of6-amino-2-[3,5-dichloro-4-([6-chloro-5-[1-(3,3-difluoro-cyclobutyl)ethyl]pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dione(280 mg, 0.539 mmol) in AcOH (8 mL) was added NaOAc (221 mg, 2.69 mmol).The mixture was stirred overnight at 100° C. The mixture reaction wascooled to rt and quenched with water (50 mL). The reaction mixture wasstirred for 10 min, the solid was filtered and washed with water (2×10mL) and PE (2×5 mL), then dried under reduced pressure to afford thecrude product that was purified by preparative HPLC to afford6-amino-2-[3,5-dichloro-4-([5-[1-(3,3-difluorocyclobutyl)ethyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-tri-azine-3,5-dioneas a white solid (34.2 mg, 13%). LCMS (ESI, m z): 523 [M+Na]⁺.

The enantiomers were separated by preparative pre-chiral-HPLC using thefollowing gradient conditions: Column: CHIRALPAK IA, 3×25 cm, 5 μm;Mobile Phase A:Hex:DCM=3:1 (10 mM NH₃—CH3OH)-HPLC, Mobile PhaseB:EtOH-HPLC; Flow rate: 40 mL/min; Gradient: 10 B to 10 B in 50 min;220/254 nm; Injection Volume: 1 mL; Number Of Runs: 14. Purificationresulted in (RT 1: 35.6 min (compound 61-A (RT 1=35.6 min, 43.9 mg) asan off-white solid, and compound 61-B (RT 2=42.1 min, 41.8 mg).

61-A: ¹H NMR (300 MHz, DMSO-d₆) δ 12.28 (br, 2H), 7.86 (s, 2H), 7.52 (s,1H), 6.54 (br, 2H), 2.99-3.04 (m, 1H), 2.73 (br, 1H), 2.51-2.60 (m, 1H),2.44-2.50 (m, 2H), 2.12-2.24 (m, 1H), 1.15 (d, J=6.9 Hz, 3H). LCMS (ESI,m z): 501 [M+H]⁺. [α]^(22.1) _(D)=+18° (MeOH, C=1 mg/mL).

And (RT 2: 42.1 min (compound 61-B), 41.8 mg)¹H NMR (300 MHz, DMSO-d₆) δ12.27 (br, 2H), 7.85 (s, 2H), 7.52 (s, 1H), 6.53 (br, 2H), 2.98-3.03 (m,1H), 2.69-2.74 (m, 1H), 2.52-2.54 (m, 1H), 2.44-2.50 (m, 2H), 2.12-2.24(m, 1H), 1.15 (d, J=6.9 Hz, 3H). LCMS (ESI, m z): 501 [M+H]⁺. [α]^(22.1)_(D)=−14° (MeOH, C=1 mg/mL).

Example 56. Synthesis of Compound 62

To a solution of 3,6-dichloropyridazine (5.00 g, 33.6 mmol) in water(100 mL) was added silver nitrate (2.85 g, 16.8 mmol) andoxolane-3-carboxylic acid (3.90 g, 33.6 mmol) in portions at rt and thenstirred at 50° C. To the mixture was added sulfuric acid (9.88 g, 101mmol) in portions at 50° C. and stirred at 60° C. Then ammoniumpersulfate (23 g, 101 mmol) in water (50 mL) was added and stirred for 1h at 70° C. The mixture was neutralized to pH 9 with NaOH solution (2N).The mixture was extracted with EA (3×50 mL). The combined organic layerswere washed with brine (50 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on asilica gel column with PE:EA (10:1) to provide3,6-dichloro-4-(oxolan-3-yl)pyridazine as a light yellow oil (2.8 g,36%).

To a solution of 3,6-dichloro-4-(oxolan-3-yl)pyridazine (330 mg, 1.51mmol) andt-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]-carbamate(586 mg, 1.51 mmol) in DMSO (10 mL) was added K₂CO₃ (625 mg, 4.52 mmol)and CuI (28.7 mg, 0.15 mmol). The reaction was stirred at 110° C. for 16h under N₂, then quenched with water (50 mL) The mixture was extractedwith EA (3×50 mL), washed with brine (30 mL), dried over anhyd. Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified on a silica gel column with MeOH:DCM (1:20) to affordt-butyl-N-[2-(3,5-dichloro-4-[[6-chloro-5-(oxolan-3-yl)pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamateas a brown solid (600 mg, 49%).

To a solution of6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(oxolan-3-yl)-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(420 mg, 0.89 mmol) in AcOH (10 mL) was added NaOAc (292 mg, 3.56 mmol).The reaction was stirred overnight at 100° C. The reaction solution waspoured into water (100 mL) and filtered. The precipitate was purified bypreparative HPLC to afford6-amino-2-(3,5-dichloro-4-[[6-hydroxy-5-(oxolan-3-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-tri-azine-3,5-dioneas a white solid (72.8 mg, 18%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.28-12.30(m, 2H), 7.86 (s, 2H), 7.50 (s, 1H), 6.54 (s, 2H), 3.80-4.01 (m, 2H),3.75-3.78 (m, 1H), 3.63-3.68 (m, 1H), 3.42-3.54 (m, 1H), 2.18-2.29 (m,1H), 1.98-2.10 (m, 1H). LCMS (ESI, m/z): 453 [M+H]⁺.

Example 57. Synthesis of Compound 63

To a solution of 3,6-dichloro-pyridazine (5.00 g, 33.6 mmol) and phenylboronic acid (8.18 g, 67.1 mmol) in water (180 mL) and1,2-dichloroethane (180 mL) was added Selectfluor™ (23.8 g, 67.1 mmol)and TFA (3.83 g, 33.6 mmol). The reaction was stirred at rt for 2 minand AgNO₃ (1.14 g, 6.71 mmol) in water (20 mL) was added. Then thereaction mixture was stirred 50° C. for 16 h. The solution was extractedwith DCM (2×200 mL). The organic layers were combined, dried over anhyd.Na₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified on asilica gel column with PE:EA (25:1) to afford3,6-dichloro-4-phenylpyridazine as a yellow solid (950 mg, 12%).

To a solution of 3,6-dichloro-4-phenylpyridazine (338 mg, 1.50 mmol) andt-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbam-ate(585 mg, 1.50 mmol) in DMSO (15 mL) was added K₂CO₃ (623 mg, 4.50 mmol)and CuI (143 mg, 0.75 mmol). The reaction mixture was stirred at 110° C.for 16 h under N₂, then quenched with water (100 mL). The mixture wasextracted with EA (3×100 mL) and the organic layers were combined,washed with brine (100 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on asilica gel column with PE:EA (2:3) to gett-butyl-N-(2-[3,5-dichloro-4-[(6-chloro-5-phenylpyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamateas a brown solid (350 mg, 32%).

To a solution of6-amino-2-[3,5-dichloro-4-[(6-chloro-5-phenylpyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(350 mg, 0.733 mmol) and in AcOH (10 mL) was added NaOAc (240 mg, 2.93mmol). The reaction was stirred overnight at 100° C. and cooled to rt.The reaction solution was poured into water (100 mL) and filtered. Theprecipitate was purified by preparative HPLC to afford6-amino-2-[3,5-dichloro-4-[(6-hydroxy-5-phenylpyridazin-3-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneas a white solid (30.4 mg, 9%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.48 (s,1H), 12.29 (s, 1H), 7.95-7.98 (m, 2H), 7.88 (s, 3H), 7.49-7.52 (m, 3H),6.55 (s, 2H). LCMS (ESI, m z): 459 [M+H]⁺.

The regioisomeric product6-amino-2-(3,5-dichloro-4-((6-oxo-4-phenyl-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(63-A) was isolated. ¹H NMR (300 MHz, DMSO-d₆) δ 12.40 (s, 1H), 12.28(s, 1H), 7.87 (s, 1H), 7.79-7.82 (m, 2H), 7.55-7.59 (m, 3H), 7.13 (s,1H), 6.53 (s, 2H).

Example 58. Synthesis of Compound 64

A 250 mL round-bottom flask was charged with Na₂CO₃ (6.00 g, 56.6 mmol),dioxane (45.0 mL), water (15 mL) under N₂. The mixture was stirred for10 min at rt. 4-Bromo-6-chloropyridazin-3-amine (5.90 g, 28.3 mmol),2-fluoro-3-methylphenylboronic acid (4.79 g, 31.1 mmol), PdCl₂(dppf)-DCMcomplex (2.31 g, 2.83 mmol) was added. The reaction was stirredovernight at 110° C. under N₂. The solids were removed by filtration.The organic layers were separated with 400 mL EA:brine (1:1). Theorganic layer was dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified on a silica gel column with EA:PE (40:60) toprovide 6-chloro-4-(2-fluoro-3-methylphenyl)pyridazin-3-amine as a brownsolid (3 g, 37%).

A 100 mL round-bottom flask was charged with t-butyl nitrite (3.38 g,32.8 mmol), cupric chloride (1.77 g, 13.1 mmol) in ACN (30.0 mL).6-Chloro-4-(2-fluoro-3-methylphenyl)pyridazin-3-amine (2.60 g, 10.9mmol) was added dropwise at 0° C. The reaction was stirred overnight at60° C. and quenched with water (20 mL). The mixture was extracted withEA (3×50 mL), washed with brine (50 mL), dried over anhyd. Na₂SO₄, thesolids were removed under reduced pressure and the filtrate wasconcentrated under reduced pressure. The residue was purified on asilica gel with EA:PE (15:85) to provide3,6-dichloro-4-(2-fluoro-3-methylphenyl)-pyridazine as an off-whitesolid (1.1 g, 37%).

A 40 mL vial was charged with3,6-dichloro-4-(2-fluoro-3-methylphenyl)-pyridazine (1.10 g, 4.28 mmol),4-amino-2,6-dichlorophenyloxidanyl (0.98 g, 5.56 mmol), K₂CO₃ (1.77 g,12.8 mmol), CuI (0.33 g, 1.71 mmol), DMSO (10 mL) under N₂. The reactionwas stirred for 16 h at 90° C. and quenched with water (20 mL). Themixture was extracted with EA (3×50 mL), dried over anhyd. Na₂SO₄, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was purified on a silica gel withEA:PE (1:5) to provide3,5-dichloro-4-[[6-chloro-5-(2-fluoro-3-methylphenyl)pyridazin-3-yl]-oxy]anilineas a brown solid (1.4 g, 78%).

A 40 mL vial was charged with3,5-dichloro-4-[[6-chloro-5-(2-fluoro-3-methylphenyl)pyridazin-3-yl]oxy]aniline(1.40 g, 3.51 mmol), NaOAc (1.73 g, 21.1 mmol), AcOH (14 mL) under N₂.The reaction was stirred overnight at 100° C. The reaction was quenchedby water (20 mL), extracted with EA (3×50 mL) and the organic layerswere washed with brine (50 mL), dried over anhyd. Na₂SO₄, filtered andconcentrated under reduced pressure. NaOH (1.40 g, 35.1 mmol)), MeOH (7mL) and water (7 mL) was added. The reaction was stirred overnight at120° C. The reaction was extracted with EA (3×50 mL) and the organiclayers were combined, washed with brine (50 mL), dried over anhyd.Na₂SO₄, the solids were removed under reduced pressure and the filtratewas concentrated under reduced pressure. The residue was purified on asilica gel column with EA:PE (3:7) to provide6-(4-amino-2,6-dichlorophenoxy)-4-(2-fluoro-3-methylphenyl)-2H-pyridazin-3-oneas a brown semi-solid (950 mg, 57%).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-(2-fluoro-3-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate,a brown solid (800 mg, 55%), was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,a brown solid (400 mg, 64%), was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

A 100 mL round-bottom flask was charged with2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrile(250 mg, 0.499 mmol), HCl (2 mL), AcOH (10 mL). The reaction was stirredfor 2 h at 120° C. and concentrated reduced pressure. The residue wasdiluted with sat. NaHCO₃ solution (20 mL), the mixture was extractedwith EA (3×30 mL) and the organic layers were discarded. The pH of theaq. layer was adjusted to 5-6 with conc. HCl. The solution was extractedwith CHCl₃:isopropanol=3:1) (3×40 mL), the organic layers were combined,dried over anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to provide2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid as an off-white solid (110 mg, 41%).

A 25 mL round-bottom flask was charged with2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-tri-azine-6-carboxylicacid (110 mg, 0.211 mmol), diphenylphosphoryl azide (174 mg, 0.634mmol), NEt₃ (85.6 mg, 0.846 mmol), tBuOH (5 mL) under N₂. The reactionwas stirred overnight at 85° C. and quenched with water (10 mL). Themixture was extracted with EA (3×30 mL), washed with brine (20 mL),dried over anhyd. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by preparatory TLC with EA:PE (4:1) to providet-butyl-N-[2-(3,5-dichloro-4-[[5-(2-fluoro-3-methyl-phenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamateas an off-white solid (80 mg, 46%).

A 50 mL round-bottom flask was charged witht-butyl-N-[2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(130 mg, 0.220 mmol), DCM (5 mL), TFA (1 mL). The reaction was stirredovernight at rt and concentrated under reduced pressure. The pH of theresidue was adjusted to 8 with NaHCO₃ (sat., aq.). The solution wasextracted with EA (3×30 mL) and the organic layers were combined, washedwith brine (30 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to provide6-amino-2-(3,5-dichloro-4-[[5-(2-fluoro-3-methylphenyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (10.3 mg, 9%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.52 (s, 0.3H), 12.29 (s, 0.3H), 7.90 (s,2H), 7.78 (s, 1H), 7.42-7.44 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 6.48-6.55(m, 2H), 2.31 (s, 3H).

LCMS (ESI, m/z): 491 [M+H]⁺.

Example 59. Synthesis of Compound 65

4-Benzyl-3,6-dichloro-pyridazine, a yellow oil (270 mg, 27%), wasprepared similarly to 3,6-dichloro-4-isopropylpyridazine.

To a solution of 4-benzyl-3,6-dichloropyridazine (270 mg, 1.13 mmol) andt-butyl-N-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbam-ate(483 mg, 1.24 mmol) in DMSO (10 mL) was added K₂CO₃ (468 mg, 3.39 mmol)and CuI (215 mg, 1.13 mmol). The reaction was stirred at 110° C. for 16h under N₂ and quenched with water (100 mL). The mixture was extractedwith EA (3×100 mL) and the organic layers were combined, washed withbrine (100 mL), dried over anhyd. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified on a silica column with MeOH:DCM (4:96) to affordt-butyl-N-(2-[4-[(5-benzyl-6-chloropyridazin-3-yl)oxy]-3,5-dichlorophenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbam-ateas a brown solid (400 mg, 36%).

To a solution of6-amino-2-[4-[(5-benzyl-6-chloropyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5-dione(240 mg, 0.49 mmol) in AcOH (6 mL) was added NaOAc (160 mg, 1.95 mmol).The reaction was stirred overnight at 100° C. and cooled to rt. Thereaction solution was poured into water (100 mL) and filtered. Theprecipitate was purified by preparative HPLC to afford6-amino-2-[4-[(5-benzyl-6-hydroxypyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5-dioneas a white solid (56.6 mg, 24%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.27-12.30 (m, 2H), 7.85 (s, 2H), 7.24-7.37(m, 6H), 6.53 (s, 2H), 3.87 (s, 2H).

LCMS (ESI, m z): 495 [M+Na]⁺.

Example 60. Synthesis of Compound 66

2-[(4-Benzyloxy-2,6-dimethyl-phenyl)methyl]-7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine as a yellow solid (770 mg, 70%) was prepared similarlyas described for5-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine.

A mixture of2-[(4-benzyloxy-2,6-dimethyl-phenyl)methyl]-7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine(610 mg, 1.13 mmol) in DCM (20 mL) and BBr3 (1.42 g, 5.65 mmol, 544.54μL) was added. The reaction mixture was degassed and purged with N₂ for3 times, and then the mixture was stirred at 0° C. for 1 h. The reactionmixture was quenched by addition NaHCO₃(15 mL) at 0° C., and thendiluted with H₂O (25 mL) and extracted with DCM (3×45 mL). The combinedorganic layers were dried over MgSO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thecrude was purified by flash silica gel chromatography (EA:PE=0-10%) toafford4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo-[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethyl-phenolas a yellow solid (400 mg, 79%).

[4-[[7-Isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine-2-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate, a white solid (430 mg, 83%) was preparedsimilarly as described for[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate.

A mixture of[4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethyl-phenyl]trifluoromethanesulfonate (280 mg, 481 μmol), t-butyl carbamate (226 mg,1.93 mmol), XantPhos (68.9 mg, 144 μmol), Pd(OAc)₂ (10.8 mg, 48.1 μmol)and Cs₂CO₃ (627 mg, 1.93 mmol) in dioxane (10 mL) was degassed andpurged with N₂, then the mixture was stirred at 100° C. for 4 h underN₂. The reaction mixture was concentrated under reduced pressure, thenthe residue was diluted with H₂O (20 mL) and extracted with EA (3×20mL). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givecrude product, which was purified by silica gel chromatography(EA:PE=0˜15%) to givet-butyl-N-[4-[[7-isopropyl-5-(p-tolylsulfonyl)-pyrrolo[2,3-b]-pyrazin-2-yl]methyl]-3,5-dimethyl-phenyl]carbamateas a yellow gum (290 mg, 76%).

To a solution oft-butyl-N-[4-[[7-isopropyl-5-(p-tolylsulfonyl)-pyrrolo-[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethyl-phenyl]carbamate(356 mg, 454 μmol) in DCM (3 mL) was added TFA (518 mg, 4.54 mmol,336.27 μL). The mixture was stirred at 20° C. for 2 h. The reactionmixture was quenched with sat. aq. NaHCO₃(5 mL) at 20° C., then dilutedwith H₂O (5 mL) and extracted with DCM (3×20 mL). The combined organiclayers were washed with brine (20 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by flash silica gel chromatography (EA:PE=0-30%) to give4-[[7-isopropyl-5-(p-tolyl-sulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-dimethyl-anilineas a yellow solid (183 mg, 89%).

EthylN-[2-cyano-2-[[4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo-[2,3-b]pyrazin-2-yl]-methyl]-3,5-dimethyl-phenyl]hydrazono]acetyl]carbamate,a yellow solid (90 mg, 47%), was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

To a solution of ethylN-[2-cyano-2-[[4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine-2-yl]methyl]-3,5-dimethyl-phenyl]hydrazono]-acet-yl]carbamate(146 mg, 237 μmol) in AcOH (15 mL) was added NaOAc (97.3 mg, 1.19 mmol).The mixture was stirred at 130° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure, adjusted to pH 7˜8 by NaHCO₃ (sat.,aq. 5 mL) then extracted with EA (3×20 mL). The combined organic layerswere washed with brine (20 mL), dried over anhyd. Na₂SO₄, the solidswere removed under reduced pressure and the filtrate was concentratedunder reduced pressure to give2-[4-[[7-isopropyl-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazin-2-yl]methyl]-3,5-di-methyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrileas a yellow solid (100 mg, crude).

Tosyl group deprotection to give2-[4-[(7-isopropyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl]-3,5-dimethyl-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile,a yellow solid (34.8 mg, 48%), was prepared similarly as described formethyl5-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4H-1,2,4-triazin-2-yl)phenoxy]-1H-indole-3-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ=12.98 (br s, 1H), 11.57 (br s, 1H), 7.96 (s,1H), 7.53 (s, 1H), 7.16 (s, 2H), 4.29 (s, 2H), 3.19-3.07 (m, 1H), 2.43(s, 6H), 1.32 (d, J=6.9 Hz, 6H). LCMS (ESI, m z): 416.3[M+H]+.

Example 61. Synthesis of Compound 67 and 67-A

A 100 mL round-bottom flask was charged with sodium carbonate (2.03 g,19.190 mmol), dioxane (20 mL) and water (4 mL). The mixture was stirredfor 10 min at rt. 4-bromo-6-chloropyridazin-3-amine (2 g, 9.595 mmol),2-naphthalene boronic acid (1.82 g, 10.555 mmol) and PdCl₂(dppf) (783.57mg, 0.960 mmol) was added. The mixture was stirred for 2 h at 110° C.under N₂. The reaction mixture was diluted with EA (20 mL) and filteredthrough packed celite, the celite pad was washed with EA (2×10 mL), andthe filtrate was washed with brine (20 mL). The organic layer was driedover anhydr. sodium sulfate, the solids were removed by filtration andthe filtrate was concentrated under reduced pressure. The residue waschromatographed on a silica gel column (PE:EA=10:1) to provide6-chloro-4-(naphthalen-1-yl)pyridazin-3-amine as a yellow solid (1.75 g,68%). LCMS (ESI, m z): 256 [M+H]⁺.

To a solution of CuCl₂ (1.10 g, 8.212 mmol) in CH₃CN (5 mL) was addedt-butyl nitrite (2.12 g, 20.531 mmol) at 0° C. was added6-chloro-4-(naphthalen-2-yl)pyridazin-3-amine (1.75 g, 6.844 mmol) inCH₃CN (15 mL) dropwise. The reaction mixture was stirred 18 h at 60° C.The reaction mixture was cooled to rt and filtered through packedcelite, the celite pad was washed with EA (3×10 mL), and then quenchedwith water (10 mL) and extracted with EA (3×20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydr. sodiumsulfate. After filtration, the filtrate was concentrated. The residuewas purified by silica gel column chromatography (EA:PE=1:10) to afford3,6-dichloro-4-(naphthalen-2-yl)pyridazine as a yellow solid (990 mg,50%). LCMS (ESI, m z): 275 [M+H]⁺.

To a solution of 3,6-dichloro-4-(naphthalen-2-yl)pyridazine (400.00 mg,1.454 mmol), t-butylN-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(565.83 mg, 1.454 mmol) and K₂CO₃ (602.79 mg, 4.362 mmol) in DMSO (8 mL)was added CuI (83.07 mg, 0.436 mmol) under N₂. The solution was stirredovernight at 110° C. then quenched with water (10 mL). The mixture wasacidified to pH ˜5 with HCl (1 M, aq.), then extracted with EA (3×30mL). The combined organic layers were washed with brine (1×20 mL), driedover anhydr. sodium sulfate, the solids were removed by filtration, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (EA:PE=1:1) to afford6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(naphthalen-2-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a red solid (300 mg, 37%). LCMS (ESI, m z): 527 [M+H]⁺.

To a solution of6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(naphthalen-2-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(300 mg, 0.568 mmol) in acetic acid (6 mL) was added NaOAc (233.16 mg,2.842 mmol). The mixture was stirred overnight at 100° C. The reactionmixture was cooled to rt, quenched with water (20 mL) and then stirredfor 10 min. The solid was filtered and washed with water (2×10 mL) andPE (2×5 mL), then dried under reduced pressure then purified bypreparative HPLC (XBridge Prep OBD C18 Column, 19×250 mm, 5 um; MobilePhase A:Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min;Gradient: 49% B to 69% B in 7 min; 220 nm) to afford6-amino-2-(3,5-dichloro-4-[[5-(naphthalen-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (40.4 mg, 14%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.55 (s,1H), 12.29 (s, 1H), 8.67 (s, 1H), 7.97-8.07 (m, 5H), 7.89 (s, 2H),7.57-7.64 (m, 2H), 6.55 (br, 2H). LCMS (ESI, m z): 509 [M+H]⁺.

6-amino-2-(3,5-dichloro-4-((4-(naphthalen-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(67-A) was isolated during the synthesis of6-amino-2-(3,5-dichloro-4-[[5-(naphthalen-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione.¹H NMR (300 MHz, DMSO-d₆) 12.44 (br, 1H), 12.27 (br, 1H), 8.38 (br, 1H),8.03-8.11 (m, 3H), 7.88-7.93 (m, 3H), 7.60-7.66 (m, 2H), 7.26 (s, 1H),6.52 (br, 2H).

Compounds 68, 69, 70, 71, 72 were prepared similarly as described inExample 61. The regioisomer products 68-A, 69-A, 70-A, 71-A, and 72-Awere also isolated.

LCMS Structure (ESI, m/z) ¹H NMR

493 [M + H]⁺ ¹H (300 MHz, DMSO-d₆) δ 12.55 (br, 1H), 12.28 (br, 1H),8.09 (s, 1H), 7.99 (s, 1H), 7.88- 7.94 (m, 3H), 7.53-7.57 (m, 2H), 6.53(s, 2H). 6-Amino-2-(3,5-dichloro-4-((5-(3- chlorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

493 [M + H]⁺ ¹H NMR (300 DMSO-d₆) δ 12.45 (s, 1H), 12.28 (s, 1H),7.85-7.88(m, 3H), 7.77 (d, J = 6.6 Hz, 1H), 7.60-7.62 (m, 2H), 7.21 (s,1H), 6.55 (s, 2H). 6-amino-2-(3,5-dichloro-4-((4-(3-chlorophenyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

477 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.46 (br, 1H), 12.28 (s, 1H),7.88 (s, 2H), 7.61-7.68 (m, 3H), 7.34-7.42 (m, 1H), 7.21 (s, 1H), 6.54(br, 2H). 6-Amino-2-(3,5-dichloro-4-((5-(3- fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

477 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.46 (br, 1H), 12.28 (s, 1H),7.88 (s, 2H),7.61-7.68 (m, 3H), 7.34-7.42 (m, 1H), 7.21 (s, 1H), 6.54(br, 2H). 6-amino-2-(3,5-dichloro-4-((4-(3- fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

473 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.28-12.45 (m, 2H), 7.84- 7.88(m, 3H), 7.74-7.77 (m, 2H), 7.30-7.40 (m, 2H), 6.54 (s, 2H), 2.08 (s,3H). 6-Amino-2-(3,5-dichloro-4-((6-oxo-5-(m-tolyl)-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

473 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.28-12.38 (m, 2H), 7.87 (s,2H),7.59-7.61 (m, 2H), 7.42-7.47 (m, 2H), 7.35- 7.37 (m, 1H), 7.10 (d, J= 2.1 Hz, 1H), 6.54 (s, 2H), 2.08 (s, 3H).6-amino-2-(3,5-dichloro-4-((6-oxo-4-(m- tolyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)- dione

487 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.29-12.45 (m, 2H), 7.79- 7.88(m, 3H), 7.77-7.79 (m, 2H), 7.33-7.43 (m, 2H), 6.54 (br, 2H), 2.64-2.74(m, 2H), 1.23 (t, J = 7.5 Hz, 3H). 6-Amino-2-(3,5-dichloro-4-((5-(3-ethylphenyl)-6-oxo-1,6-dihydro-pyridazin-3-yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

487 [M + H]⁺ ¹H NMR (300 MHz, DMSO- d₆) δ 12.28-12.38 (m, 2H), 7.87 (s,2H), 7.61-7.65 (m, 2H), 7.45-7.50 (m, 1H), 7.38- 7.41 (m, 1H), 7.11 (d,J = 1.8 Hz, 1H), 6.54 (s, 2H), 2.67- 2.74 (m, 2H), 1.19-1.26 (m, 3H).6-Amino-2-(3,5-dichloro-4-((4-(3- ethylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.23-12.41 (m, 2H), 7.87 (s,2H), 7.80 (s, 1H), 7.67- 7.69 (m, 2H), 7.14-7.17 (m, 1H), 6.53 (br, 2H),2.77 (br, 4H), 1.76 (br, 4H). 6-Amino-2-(3,5-dichloro-4-((6-oxo-5-(5,6,7,8-tetrahydro-naphthalen-2-yl)-1,6-dihydro-pyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.34-12.42 (m, 2H), 7.86 (s,2H), 7.48-7.52 (m, 2H), 7.21-7.23 (m, 1H), 7.06 (s, 1H), 6.53 (br, 2H),2.78 (br, 4H), 1.76 (br, 4H). 6-amino-2-(3,5-dichloro-4-[[6-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4- triazine-3,5-dione

Example 62: Synthesis of Compound 73

6-Amino-2-(4-((5-(t-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione was prepared similarly as described for6-amino-2-(3,5-dichloro-4-[[5-(oxan-4-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione.¹H NMR (300 MHz, DMSO-d₆) δ 12.29 (s, 1H), 12.13 (s, 1H), 7.86 (s, 2H),7.33 (s, 1H), 6.54 (s, 2H), 1.35 (s, 9H). LCMS (ESI, m z): 439 [M+H]⁺.

Example 63: Synthesis of Compound 74

3-Chloro-7-(4-methoxybenzyl)-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-c]pyridazin-6-onewas prepared according to the literature procedure (Tet. Lett. 2015, 56,772-774).

A mixture of3-chloro-7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-one(6 g, 18.88 mmol),N-(3,5-dichloro-4-hydroxy-phenyl)-N,N-dimethyl-formamidine (4.40 g,18.88 mmol), Pd(dbtpf)Cl₂ (1.23 g, 1.89 mmol), Cs₂CO₃ (18.46 g, 56.64mmol) in dioxane (100 mL) was degassed and purged with N₂ for 3 times.The mixture was stirred at 100° C. for 16 h under N₂. The reactionmixture was diluted with H₂O (200 mL) and extracted with EA (3×150 mL).The combined organic layers were washed with brine (200 mL), dried overNa₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The crude was purified by silicagel chromatography (EA:PE=0-50%) to giveN-[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3-c]pyrida-zin-3-yl]oxy-phenyl]-N,N-dimethyl-formamidineas a brown solid (6.5 g, 67%).

To a solution ofN′-[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3-c]pyridazin-3-yl]oxy-phenyl]-N,N-dimethyl-formamidine(4.5 g, 8.75 mmol) in 2-propanol (80 mL) was added NH₂NH₂ hydrate (4.38g, 87.48 mmol, 4.25 mL) at 20° C. After the addition, the mixture wasstirred at 80° C. for 16 h. The reaction mixture was quenched by H₂O(160 mL) and extracted with EA (3×100 mL). The combined organic layerswere washed with brine (3×50 mL), dried over Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The crude product was purified by flash silica gelchromatography (EA in PE: 0˜50%) to afford3-(4-amino-2,6-dichloro-phenoxy)-7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-pyrrolo[2,3-c]pyridazin-6-oneas awhite solid (3.2 g, 80%).

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((7-(4-methoxybenzyl)-5,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazin-3-yl)oxy)phenyl)hydrazine-ylidene)acetyl)carbamate(6.46 g, 5.16 mmol, 74%, 50% purity), an orange solid, was preparedsimilarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate.

To a solution of ethylN-[2-cyano-2-[[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3-c]pyridazin-3-yl]oxy-phenyl]hydrazono]acetyl]carbamate(6.46 g, 5.16 mmol) in DMF (60 mL) was added Et₃N (2.61 g, 25.78 mmol,3.59 mL) in one portion at 20° C. The mixture was stirred at 90° C. for16 h. The reaction mixture was diluted with H₂O (150 mL) and extractedwith EA (3×150 mL). The combined organic layers were washed with brine(3×100 mL), dried over Na₂SO₄, the solids were removed by filtration andthe filtrate was concentrated under reduced pressure. The crude productwas purified by flash chromatography (MeOH:DCM=0˜5%) to afford2-[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3-c]pyridazin-3-yl]oxy-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrileas a brown solid (4.1 g, 96%).

To a solution of2-[3,5-dichloro-4-[7-[(4-methoxyphenyl)methyl]-5,5-dimethyl-6-oxo-pyrrolo[2,3-c]pyridazin-3-yl]oxy-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(780 mg, 1.34 mmol) in ACN (10 mL) and H₂O (10 mL) was added CAN (2.21g, 4.03 mmol, 2.01 mL) at 0° C. The mixture was stirred at 25° C. for 2h. The reaction mixture was diluted with H₂O (20 mL) and extracted withEA (3×30 mL). The combined organic layers were washed with brine (3×20mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by preparative HPLC([Column: Welch Xtimate C18 150×30 mm×5 um; Mobile phase: from 15% ACNin water (0.225% NH₃.H2O) to 45% ACN in water (0.225% NH₃.H₂O)]) to give2-[3,5-dichloro-4-[(5,5-dimethyl-6-oxo-7H-pyrrolo[2,3-c]pyridazin-3-yl)oxy]phenyl]3,5-dioxo-1,2,4-triazine-6-carbonitrileas a white solid (61.1 mg, 10%). ¹H NMR (400 MHz, DMSO-d₆) δ=11.55 (brs, 1H), 7.82 (s, 1H), 7.80 (s, 2H), 7.09 (br s, 3H), 1.39 (s, 6H). LCMS(ESI, m z): 460.1[M+H]⁺.

Example 64: Synthesis of Compound 75

To a solution of 2,2,6,6-tetramethylpiperidine (4.55 g, 32.22 mmol, 5.47mL) in THF (20 mL) at −30° C. was added dropwise n-BuLi (2.5 M, 11.28mL) over 30 min. After addition, the mixture was stirred at −30° C. for30 min, and then 3,6-dichloropyridazine (3 g, 20.14 mmol) and2-methylpropanal (1.60 g, 22.15 mmol, 2.02 mL) in THF (20 mL) was addeddropwise at −65° C. The mixture was stirred at −65° C. for 1 h. Thereaction mixture was quenched by NH₄C₁ (sat., aq., 10 mL) at −60° C. Themixture was worked up with a previous batch and then diluted with H₂O(100 mL) and extracted with EA (100 mL×3). The combined organic layerswere washed with brine (80 mL), dried over Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The crude product was purified by silica gel chromatography(EA:PE=0-15%) to afford1-(3,6-dichloropyridazin-4-yl)-2-methylpropan-1-ol as a yellow liquid(3.34 g, 15%).

To a suspension of NaH (4.11 g, 102.68 mmol, 60% purity) in THF (40 mL)was added 1-(3,6-dichloropyridazin-4-yl)-2-methylpropan-1-ol (2.27 g,10.27 mmol) and TBSCl (3.10 g, 20.54 mmol, 2.52 mL) in THF (10 mL) at 0°C. The mixture was stirred at 0° C. for 1 hr. The reaction mixture wasquenched with H₂O (10 mL), then diluted with H₂O (50 mL) and extractedwith EA (3×50 mL). The combined organic layers were washed with brine(3×50 mL), dried over anhydr. Na₂SO₄, filtered and concentrated underreduced pressure to give a residue, which was purified by flash silicagel chromatography (0˜5% EA in PE) to afford4-(1-((t-butyldimethylsilyl)oxy)-2-methylpropyl)-3,6-dichloropyridazineas a yellow liquid (2.49 g, 72%).

To a solution of 4-amino-2,6-dichloro-phenol (3 g, 16.85 mmol) intoluene (30 mL) was added DMF-DMA (2.21 g, 18.54 mmol, 2.46 mL). Afterthe addition, the mixture was stirred at 100° C. for 2 h. The mixturewas concentrated to give a residue, which was triturated (PE:EA=6:1) togive N-(3,5-dichloro-4-hydroxyphenyl)-N,N-dimethylformimidamide as abrown solid (4.05 g).

N′-(4-((5-(1-((t-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-chloro-pyridazin-3-yl)oxy)-3,5-dichlorophenyl)-N,N-dimethylformimidamide(3.86 g, 74%), a yellow solid, was prepared similarly as described for3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline with theexception that the reaction was heated for 16 h at 90° C.

N′-(4-((5-(1-((t-Butyldimethylsilyl)oxy)-2-methylpropyl)-6-chloro-pyridazin-3-yl)oxy)-3,5-dichlorophenyl)-N,N-dimethylformimidamide(3.85 g, 6.84 mmol) in THF (30 mL) was added TBAF (1 M, 13.68 mL) at 25°C. and the mixture was stirred at 25° C. for 6 h. The mixture wasquenched with NH₄Cl (sat., aq., 50 mL) and extracted with EA (3×50 mL).The combined organic layers were washed with brine (50 mL), dried overanhydr. Na₂SO₄, filtered and concentrated to giveN′-(3,5-dichloro-4-((6-chloro-5-(1-hydroxy-2-methylpropyl)pyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamide (3.67 g, crude) as a yellow solid.

N′-(3,5-Dichloro-4-((6-chloro-5-(1-hydroxy-2-methylpropyl)pyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamide(3.6 g, crude) in DCM (40 mL) was added Dess-Martin reagent (6.84 g,16.12 mmol, 4.99 mL) at 25° C. in one portion and the mixture wasstirred at 25° C. for 2 h. The mixture diluted with NaHCO₃ (sat., aq.,50 mL) and extracted with DCM (2×50 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydr. Na₂SO₄, the solidswere removed by filtration and the filtrate was concentrated underreduced pressure to give a residue, which was purified by combi flash(EA:PE=0-40%) to giveN-(3,5-dichloro-4-((6-chloro-5-isobutyrylpyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamideas a yellow oil (2.23 g, 53%).

To a solution ofN′-(3,5-dichloro-4-((6-chloro-5-isobutyrylpyridazin-3-yl)oxy)phenyl)-N,N-dimethylformimidamide(1.3 g, 3.13 mmol) in 2-propanol (20 mL) was added NH₂NH₂ hydrate (5.4g, 107.87 mmol, 5.24 mL) and the mixture was stirred at 90° C. for 72 hunder N₂. The mixture was diluted with H₂O (50 mL) and extracted with EA(3×50 mL). The combined organic layers were washed with brine (50 mL),dried over anhydr. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to give a residue,which was purified by silica column chromatography (EA in PE: 0˜40%) toafford3,5-dichloro-4-[(3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy]anilineas a yellow solid (435 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.83 (s,1H), 8.03 (s, 1H), 6.71 (s, 2H), 5.63 (s, 2H), 3.45-3.36 (m, 1H), 1.37(d, J=6.9 Hz, 6H). LCMS (ESI, m z): 338[M+H]⁺.

Ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(960 mg), a yellow solid, was prepared similarly as described for ethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate, and was used in the subsequent step without furtherpurification.

2-(3,5-Dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(compound 75A, 910 mg, 76%), a red solid, was prepared similarly asdescribed for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrilewith the exception that the reaction mixture was heated at 120° C. for12 h and that NaOAc was used. ¹H NMR (400 MHz, DMSO-d₆) δ=13.97 (s, 1H),13.28 (br s, 1H), 8.31 (s, 1H), 7.82 (s, 2H), 3.46-3.39 (m, 1H), 1.40(d, J=7.0 Hz, 6H). LCMS (ESI, m z): 459[M+H]⁺.

2-(3,5-Dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (415 mg, 37%), a yellow solid, was prepared similarly as describedfor2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid, which used in next step without further purification. LCMS (ESI, mz): 478[M+H]⁺.

To a solution of2-(3,5-dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (410 mg, 0.857 mmol) in DMF (8 mL) was added Et₃N (260 mg, 2.57mmol, 0.357 mL) at 0° C., followed by slow addition of DPPA (472 mg,1.71 mmol, 0.371 mL) under N₂. The mixture was stirred at 25° C. for 3h. Then H₂O (1 mL) was added and the reaction was heated at 100° C. foradditional 2 h. The mixture was diluted with H₂O (50 mL) and extractedwith EA (3×30 mL). The combined organic layers were washed with brine(50 mL), dried over anhydr. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thecrude was purified by preparative HPLC [Phenomenex Luna C18 100×30 mm×5um; Mobile phase: from 35% ACN in water (0.225% FA) to 65% ACN in water(0.225% FA)] to give6-amino-2-(3,5-dichloro-4-((3-isopropyl-1H-pyrazolo[3,4-c]pyridazin-5-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione as a white solid (120 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆)δ=13.92 (s, 1H), 12.28 (br s, 1H), 8.24 (s, 1H), 7.89 (s, 2H), 6.52 (s,2H), 3.47-3.38 (m, 1H), 1.40 (d, J=7.0 Hz, 6H). LCMS (ESI, m z):449.1[M+H]⁺.

Example 65: Synthesis of Compound 76

6-Amino-2-(3,5-dichloro-4-((5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione, a white solid (95.2 mg, 27%) was prepared similarly asdescribed for6-amino-2-(3,5-dichloro-4-[[5-(oxan-4-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione.¹H NMR (400 MHz, DMSO-d₆) δ 12.25-12.27 (m, 2H), 7.85 (s, 2H), 7.42 (s,1H), 6.52 (s, 2H), 3.68-3.71 (m, 2H), 3.13-3.20 (m, 1H), 1.68-1.74 (m,2H), 1.50-1.58 (m, 1H), 1.40 (t, J=12.6 Hz, 1H), 1.25 (s, 3H), 1.19 (s,3H). LCMS (ESI, m z): 495 [M+H]⁺.

Example 66: Synthesis of Compound 77

A 500 mL round-bottom flask was charged with2,2,6,6-tetramethylpiperidine (6.20 g, 43.9 mmol) in THF (60 mL) underN₂. n-BuLi (12.1 mL, 30.2 mmol) was added dropwise at −75° C. Themixture was warmed to 0° C. and stirred for 30 min. Then the mixture wascooled to −75° C. and 3,6-dichloropyridazine (3.00 g, 20.1 mmol) in THF(60 mL) was added dropwise. The mixture was stirred for 30 min at −75°C. Cyclopentanecarboxaldehyde (5.93 g, 60.4 mmol) in THF (30 mL) wasadded dropwise. The reaction was stirred for 90 min at −75° C., thenquenched with NH₄C₁ (sat., aq., 100 mL) and extracted with EA (3×100mL), the combined organic layers were washed with brine (2×50 mL), driedover anhydr. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waspurified by reverse phase chromatography using a C18 column(MeCN:water+0.05% TFA)=85:15) to provide(6-chloro-3-methoxypyridazin-4-yl)(cyclopentyl)methanol as a yellow oil(1.7 g, 30%). LCMS (ESI, m z): 247 [M+H]⁺.

A 100 mL round-bottom flask was charged withcyclopentyl(3,6-dichloropyridazin-4-yl)methanol (1.40 g, 5.66 mmol),imidazole (1.54 g, 22.7 mmol), t-butyldimethylsilyl chloride (2.56 g,17.0 mmol), DMF (15 mL) under N₂. The reaction was stirred overnight atrt. The reaction was quenched with water (10 mL), then extracted with EA(3×30 mL), washed with brine (30 mL), dried over anhydr. Na₂SO₄,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column with (EA:PE=3:97) to provide4-[[(t-butyldimethylsilyl)oxy]-(cyclopentyl)methyl]-3,6-dichloropyridazineas a colorless oil (1.3 g, 63%). LCMS (ESI, m z): 361 [M+H]⁺.

An 8 mL vial was charged with4-[[(t-butyldimethylsilyl)oxy](cyclopentyl)methyl]-3,6-dichloropyridazine(1.30 g, 3.60 mmol), t-butylN-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(1.40 g, 3.60 mmol), CuI (342 mg, 1.80 mmol), K₂CO₃ (1.24 g, 9 mmol),DMSO (20 mL) under N₂. The reaction was stirred overnight at 110° C. andquenched with water (80 mL). The solids were removed by filtration. Thefiltrate was extracted with EA (3×100 mL) and the organic layers werecombined, washed with brine (2×50 mL), dried over anhydr. Na₂SO₄, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn (EA:PE=15:85) to provide6-amino-2-[4-[(5-[[(t-butyldimethylsilyl)oxy]-(cyclopentyl)methyl]-6-chloropyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5-dioneas a brown solid (360 mg, 14%). LCMS (ESI, m z): 613 [M+H]⁺.

A 40 mL vial was charged with6-amino-2-[4-[(5-[[(t-butyl-dimethylsilyl)oxy](cyclopentyl)methyl]-6-chloropyridazin-3-yl)oxy]-3,5-dichloro-phenyl]-4H-1,2,4-triazine-3,5-dione(170 mg, 0.277 mmol), NaOAc (90.8 mg, 1.11 mmol), CH₃CO₂H (5 mL) underN₂. The reaction was stirred overnight at 110° C. The pH value of thesolution was adjusted to 8.0 with NaHCO₃ (sat., aq.). The solution wasextracted with DCM (3×20 mL) and the organic layers were combined,washed with brine (2×10 mL), dried over anhydr. Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The product was dissolved into CH₃OH (2 mL). NaOH (55.4 mg,1.38 mmol) in water (2 mL) was added. The reaction was stirred for 2 hat 50° C. The reaction was quenched with H₂O (10 mL), then extractedwith EA (3×20 mL). The organic layers were combined, washed with brine(2×10 mL), dried over anhydr. Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure toafford6-amino-2-[4-[(5-[[(t-butyldimethylsilyl)oxy](cyclopentyl)methyl]-6-oxo-1H-pyridazin-3-yl)oxy]-3,5-dichlorophenyl]-4H-1,2,4-triazine-3,5-dioneas a brown solid (150 mg, 57%). LCMS (ESI, m z): 595 [M+H]⁺.

6-amino-2-[3,5-dichloro-4-([5-[cyclopentyl(hydroxy)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dione,a white solid (3.4 mg) was prepared similarly as described for2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-4H-1,2,4-tri-azine-6-carbonitrileexcept that the reaction with TBAF occurred at rt. ¹H NMR (300 MHz,DMSO-d₆) δ 12.27 (br, 1H), 7.88 (s, 2H), 7.40 (s, 1H), 6.34 (br, 2H),5.41 (d, J=4.8 Hz, 1H), 4.63 (br, 1H), 2.22 (br, 1H), 1.44-1.57 (m, 8H).LCMS (ESI, m z): 481 [M+H]⁺.

Example 67: Synthesis of Compounds 78 and 79

To a solution of 1-(benzyloxy)-2-bromobenzene (10 g, 38.003 mmol) andsodium amide (4.45 g, 114.010 mmol) in THF (150 mL) was added1,1-diethoxyethene (13.24 g, 114.010 mmol) under N₂. The reaction wasstirred at 70° C. for 16 h. The solution was poured into ice water (100mL), acidified with concentrated hydrochloric acid (25 mL), andextracted with EA (2×200 mL). The organic layers were combined, driedover anhydr. Na₂SO₄, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The residue waschromatographed on a silica gel column (EA:PE=1:50) to afford5-(benzyloxy)bicyclo[4.2.0]octa-1(6), 2,4-trien-7-one as a white solid(3.3 g, 37%). GCMS (ESI, m z): 224 [M].

To a solution of 5-(benzyloxy)bicyclo[4.2.0]octa-1(6), 2,4-trien-7-one(9 g, 40.132 mmol) in CH₃OH (250 mL) was added NaBH₄ (3.036 g, 80.264mmol). The reaction was stirred at rt for 4 h. The reaction was quenchedwith water and extracted with EA (2×200 mL). The organic layers werecombined, dried over anhydr. Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel column(EA:PE=1:15) to get 5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-olas a white solid. GCMS (ESI, m z): 226 [M]. (7.4 g, 77%).

To a solution of iodine (11.41 g, 44.945 mmol) in toluene (90 mL) wasadded triphenylphosphine (10.22 g, 38.953 mmol). The reaction wasstirred at rt for 5 min under N₂ and imidazole (6.12 g, 89.891 mmol) wasadded. The mixture was stirred at rt for 10 min and5-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-trien-7-ol (3.39 g, 14.982mmol) in toluene (30 mL) was added. The solution was stirred at rt for 1h and quenched with sodium sulfite (sat., aq., 100 mL). The mixture wasextracted with EA (100 mL×3), dried over anhydr. Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was chromatographed on a silica gel column(EA:PE=1:50) to get2-(benzyloxy)-8-iodobicyclo[4.2.0]octa-1(6),2,4-triene as a yellow oil.GCMS (ESI, m z): 336 [M]. (4.46 g, 84%).

To a solution of LiAlH₄ (4.01 g, 105.601 mmol) in THF (100 mL) was added2-(benzyloxy)-8-iodobicyclo[4.2.0]octa-1(6),2,4-triene (14.20 g, 42.240mmol) in THF (150 mL) dropwise. The reaction mixture was stirred at rtfor 30 min and quenched with ice water (200 mL) and adjusted to pH=5with concentrated hydrochloric acid. The mixture was extracted with EA(3×200 mL) and the organic layers was combined, washed with brine (100ml) dried over anhydr. Na₂SO₄, filtered and concentrated under reducedpressure to get 2-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-triene as acolorless oil. GCMS (ESI, m z): 210 [M]. (8.900 g, 90%).

A solution of 2-(benzyloxy)bicyclo[4.2.0]octa-1(6),2,4-triene (7g,33.290 mmol) in methanol (175 mL) was added Pd/C (3 g). The reactionwas stirred for 16 h at rt under hydrogen and filtered. The filtrate wasconcentrated under reduced pressure. The residue was chromatographed ona silica gel column (EA:PE=1:20) to getbicyclo[4.2.0]octa-1(6),2,4-trien-2-ol as a colorless oil. LCMS (ESI, mz): 119 [M−H]. (1.66 g, 35%).

To a solution of bicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (1 g, 8.323mmol) and diisopropylamine (84.22 mg, 0.832 mmol) in DCM (37.50 mL) wasadded sulphone chloride (1123.34 mg, 8.323 mmol) in DCM (10 mL) dropwiseat 0° C. The reaction was stirred at rt for 16 h and quenched with water(100 mL). The mixture was extracted with DCM (3×50 mL), washed withbrine, dried over anhydr. Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel column(EA:PE=1:50) to 3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol as ayellow oil (760 mg, 51%). LCMS (ESI, m z): 153 [M−H]⁻.

To a solution of 3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (800 mg,5.175 mmol) in acetic acid (22 mL) was added HNO₃ (326.09 mg, 5.175mmol) in acetic acid (2 mL) at 0° C. The reaction was stirred at rtovernight and quenched with water (100 mL). The reaction mixture wasextracted with EA (3×50 mL), washed with brine, dried over anhydr.Na₂SO₄, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column with (EA:PE=1:50) to get3-chloro-5-nitrobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (500 mg, 41%) asa yellow solid. LCMS (ESI, m z): 198 [M−H]⁻.

To a solution of 3-chloro-5-nitrobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol(500.00 mg, 2.505 mmol) in ethanol (20 mL) and H₂O (10 mL) was added Fe(699.50 mg, 12.526 mmol) and NH₄Cl (1.072 g, 20.041 mmol). The mixturewas stirred for 5 h at 60° C. The mixture was filtered, the filter cakewas washed with DCM (6×50 mL). The filtrate was extracted withdichloromethane (3×300 mL). The combined organic layers were dried overanhydr. Na₂SO₄. The solids were removed by filtration, the filtrate wasconcentrated under reduced pressure to afford5-amino-3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-ol (450 mg, 95%) asa brown solid. LCMS (ESI, m z): 170 [M+H]⁺.

4-Chloro-5-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]bicyclo[4.2.0]octa-1(6),2,4-trien-2-amine(640 mg, 72%), a yellow oil, LCMS (ESI, m z): 324 [M+H]⁺, was preparedsimilarly as described for3,5-dichloro-4-[(6-chloro-5-isopropylpyridazin-3-yl)oxy]aniline.

6-([5-Amino-3-chlorobicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]oxy)-4-isopropyl-2H-pyridazin-3-one(300 mg, 52%), a brown solid, LCMS (ESI, m z): 306 [M+H]⁺, was preparedsimilarly as described for6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one.

Ethyl(2-(2-(4-chloro-5-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)hydrazineylidene)-2-cyanoacetyl)-carbamate(250 mg, 77%), a yellow solid, was prepared similarly as described forethyl(2-cyano-2-(2-(3,5-dichloro-4-((1-tosyl-1H-indol-5-yl)oxy)phenyl)-hydrazineylidene)-acetyl)carbamate. LCMS (ESI, m z): 473 [M+H]⁺.

2-[4-Chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,compound 78 was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbo-nitrile,and was isolated as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (s,1H), 7.37 (s, 1H), 6.90-7.20 (br, 2H), 2.96-3.13 (m, 5H), 1.18 (d, J=6.9Hz, 6H). LCMS (ESI, m z): 427 [M+H]*), was prepared similarly asdescribed for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile.

2-[4-Chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]bicyclo-[4.2.0]octa-1(6),2,4-trien-2-yl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (180 mg, 82%), a white solid (LCMS (ESI, m z): 446 [M+H]⁺), wasprepared similarly as described for2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid.

N-(2-[4-Chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)carbamate(200 mg, 81%), a yellow oil (LCMS (ESI, m z): 517 [M+H]⁺) was preparedsimilarly as described for t-butylN-(2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl)-carbamate.

6-Amino-2-[4-chloro-5-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl]-4H-1,2,4-triazine-3,5-dione(92.5 mg, 56%), a white solid, compound 79 (¹H NMR (300 MHz, DMSO-d₆) δ12.20-12.27 (m, 2H), 7.58 (s, 1H), 7.31 (s, 1H), 6.46 (s, 2H), 3.16 (br,2H), 2.99-3.08 (m, 1H), 2.95 (br, 2H), 1.18 (d, J=6.9 Hz, 6H). LCMS(ESI, m z): 417 [M+H]⁺) was prepared similarly as described for6-amino-2-[3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione.

Example 68: Synthesis of Compounds 80 and 81

The synthesis of6-amino-2-(3-bromo-5-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(white solid, 203.7 mg, 57%), and6-amino-2-(3,5-dibromo-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewere prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewith the exception that 4-amino-2-bromo-6-chlorophenol was employedinstead of 4-amino-2,6-dichlorophenol in the synthesis of compound 80,and 4-amino-2,6-dibromophenol was employed instead of4-amino-2,6-dichlorophenol in the synthesis of compound 81.

LCMS Structure (ESI, m/z) ¹H NMR

469 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.20 (br, 1H), 7.97 (s, 1H),7.88 (s, 1H), 7.42 (s, 1H), 6.51 (br, 2H), 3.01-3.10 (m, 1H), 1.20 (d, J= 6.6 Hz, 6H). 6-Amino-2-(3-bromo-5-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin- 3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.20-12.26 (m, 2H), 7.99 (s,2H), 7.41 (s, 1H), 6.52 (br, 2H), 3.03- 3.08 (m, 1H), 1.20 (d, J = 6.6Hz, 6H). 6-Amino-2-(3,5-dibromo-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin- 3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Example 69: Synthesis of Compound 82

5-Bromo-3,3-dimethyl-1H-indol-2-one (3.7 g, 67%), a yellow solid, wasprepared similarly as described in the procedures of WO2000066167 andWO2000066556. LCMS (ESI, m z): 240 [M+H]⁺.

A 50-mL round-bottom flask was charged with5-bromo-3,3-dimethyl-1H-indol-2-one (1.50 g, 6.247 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane(4.23 g, 18.742 mmol), potassium acetate (1.84 g, 18.742 mmol), DMSO (20mL), PdCl₂(PPh₃)₂ (438.50 mg, 0.625 mmol) under N₂. The mixture wasstirred for 2 h at 60° C. under N₂. The solution was purified by C₁₈reverse phase chromatography to provide3,3-dimethyl-2-oxo-1H-indol-5-ylboronic acid (1.2 g, 89%) as a whitesolid. LCMS (ESI, m z): 206 [M+H]⁺.

A 100-mL 3-necked round-bottom flask was charged with t-butylN-[4-[(benzyloxy)methyl]-2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(1.20 g, 2.356 mmol), 3,3-dimethyl-2-oxo-1H-indol-5-ylboronic acid (2.42g, 11.780 mmol), Cu(OAc)₂ (855.86 mg, 4.712 mmol), pyridine (372.72 mg,4.712 mmol), dichloromethane (100 mL), 4 Å molecular sieves (500 mg)under 02. The reaction was stirred for 3 days at rt. The solids werefiltered out. The organic layer was concentrated under reduced pressure.The residue was chromatographed on a C₁₈ column (CH₃CN:H₂O+0.05%TFA=7:3) to provide t-butylN-[4-[(benzyloxy)-ethyl]-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamateas a yellow solid (830 mg, 45%). LCMS (ESI, m z): 668 [M+H]⁺.

A 50-mL round-bottom flask was charged with t-butylN-[4-[(benzyloxy)methyl]-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indol-5-yl)oxy]-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(500 mg, 0.748 mmol), DCM (10 mL) under N₂. BBr₃ (1.499 g, 5.983 mmol)was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h.The reaction mixture was added dropwise to methanol (5 mL) at 0° C. andconcentrated under reduced pressure at 0° C. The crude was dissolved inmethanol (5 mL) and purified by preparative HPLC using the followinggradient conditions: XBridge Prep OBD C₁₈ Column, 19×250 mm, 5 um;Mobile Phase A:Water (10 mmol/L NH₄HCO_(3+0.1)% NH₃.H₂O), Mobile PhaseB:ACN; Flow rate: 25 mL/min; Gradient:20 B to 40 B in 7 min; 220 nm;RT1:6.42; Injection Volume: 6 ml; Purification afforded6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneas a white solid (59.4 mg, 18%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.25 (br,1H), 10.27 (s, 1H), 7.90 (s, 2H), 7.05 (d, J=2.4 Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 6.54 (br, 2H), 6.45-6.49 (m, 1H), 1.25 (s, 6H). LCMS (ESI, mz): 448 [M+H]⁺.

Example 70: Synthesis of Compound 83

A 50-mL round-bottom flask was charged with5′-bromo-1′H-spiro[cyclopentane-1,3′-indol]-2′-one (prepared accordingto the procedure in J. Med. Chem. 2008, 51, 1861-1873, 1 g, 3.757 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane(2.55 g, 11.289 mmol), potassium acetate (1.11 g, 11.272 mmol),PdCl₂(PPh₃)₂ (263.8 mg, 0.375 mmol), dimethyl sulfoxide (25 mL) underN₂. The resulting solution was stirred for 3 h at 60° C. The solutionwas purified by reverse phase column chromatography (C18,H₂O:CH₃CN=13:87) to provide2′-oxo-1′H-spiro[cyclopentane-1,3′-indol]-5′-ylboronic acid as a yellowsolid (1.07 g, 74%). LCMS (ESI, m z): 232 [M+H]⁺.

The subsequent coupling reaction, deprotection, and purification wereprepared similarly as described for6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneto afford6-amino-2-(3,5-dichloro-4-[1′H-spiro[cyclopentane-1,3′-indol]-2′-oneoxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a white solid (11.3 mg, 13%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.23 (s,1H), 7.91 (s, 2H), 6.96 (s, 1H), 6.72-6.75 (m, 1H), 6.43-6.48 (m, 3H),1.89-2.01 (m, 6H), 1.70-1.81 (m, 2H). LCMS (ESI, m z): 474 [M+H]⁺.

Example 71: Synthesis of Compound 84

3-Isopropyl-3-methyl-1H-indol-2-one was obtained as a yellow solid afterfollowing the preparation outlined in Molecules 2017, 22, 1-18. LCMS(ESI, m z): 190 [M+H]⁺.

A 40 mL vial was charged with 3-isopropyl-3-methyl-1H-indol-2-one (2.80g, 14.8 mmol), NaOAc (1.23 g, 14.9 mmol), acetic acid (30 mL). Br₂ (0.77mL, 4.84 mmol) in acetic acid (10 mL) was added dropwise. The reactionwas stirred for 50 min at rt and concentrated under reduced pressure.The residue was chromatographed on a silica gel column (EA:PE=25:75) toprovide 5-bromo-3-isopropyl-3-methyl-1H-indol-2-one as a white solid (4g, 95%). LCMS (ESI, m z): 268 [M+H]⁺.

The subsequent formation of the boronic acid, the coupling reaction,deprotection, and purification were prepared similarly as described for6-amino-2-[3,5-dichloro-4-[(3,3-dimethyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dioneto afford6-amino-2-[3,5-dichloro-4-[(3-isopropyl-3-methyl-2-oxo-1H-indol-5-yl)oxy]phenyl]-4H-1,2,4-triazine-3,5-dione(52.8 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 10.28 (s,1H), 7.89 (s, 2H), 6.86 (d, J=2.8 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H),6.54-6.58 (m, 3H), 1.91-2.00 (m, 1H), 1.23 (s, 3H), 0.85 (d, J=7.2 Hz,3H), 0.70 (d, J=6.8 Hz, 3H). LCMS (ESI, m z): 476 [M+H]⁺.

Example 72: Synthesis of Compound 85

6-Amino-2-(3,5-dichloro-4-[1′H-spiro[cyclohexane-1,3′-indol]-2′-oneoxy]phenyl)-4H-1,2,4-triazine-3,5-dione,a white solid (¹H NMR (300 MHz, DMSO-d₆) δ 10.26 (s, 1H), 7.90 (s, 2H),7.12 (s, 1H), 6.76 (d, J=4.8 Hz, 1H), 6.49-6.53 (m, 3H), 1.86 (br, 2H),1.53-1.62 (m, 8H). LCMS (ESI, m z): 488 [M+H]⁺) was prepared similarlyas described for6-amino-2-(3,5-dichloro-4-[1′H-spiro[cyclopentane-1,3′-indol]-2′-oneoxy]phenyl)-4H-1,2,4-triazine-3,5-dione.

Example 73: Synthesis of Compounds 86 to 89

Compound 86 was prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewhere 3-methylcyclobutane-1-carboxylic acid was employed instead ofcyclobutane carboxylic acid. Compound 86 was purified by SFC-HPLC[Column: (R,R)-Whelk-01, 2.12×25 cm, 5 μm; Mobile Phase A: Hex (0.1%FA)-HPLC, Mobile Phase B:EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20 Bto 20 B in 41 min; 254/220 nm] to afford compound 86-A (RT1=31.945, 10.8mg, 98% pure, SFC analytical Column: (R,R)-Whelk, 0.46×5 cm; 3.5 μm, Hex(0.1% FA):EtOH=75:25, 1.0 mL/min, Rt: 3.788 min), and compound 86-B(RT2=37.638, 7.1 mg, 98% pure, SFC Column: (R,R)-Whelk, 0.46×5 cm; 3.5μm, Hex (0.1% FA): EtOH=75:25, 1.0 mL/min, Rt: 4.378 min), both as awhite solids.

Compounds 87-A and 87-B were prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewith the exception that 3-(benzyloxy)cyclobutane-1-carboxylic acid wasemployed instead of cyclobutane carboxylic acid.6-amino-2-(4-((5-(3-(benzyloxy)cyclobutyl)-6-oxo-1,6-dihydro-pyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dionewas isolated by preparative HPLC (Column: Xcelect CSH F-pheny OBDColumn, 19×250 mm, 5 μm; Mobile Phase A:Water (10 mmol/L NH₄HCO₃),Mobile Phase B:ACN; Flow rate:25 mL/min; Gradient:26 B to 46 B in 9 min;220 nm; RT:8.85 min). This was followed by chiral preparative HPLC(Column: CHIRALPAK IC, 2×25 cm, 5 μm; Mobile Phase A:Hex (0.1% FA)-HPLC,Mobile Phase B:EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 40 B to 40 Bin 25 min; 220/254 nm; RT:10.881 min; Injection Volume:0.6 ml; Number OfRuns: 25) to afford compound 87-A as a white solid (150 mg, 23%). Anadditional separation on the racemic mixture was required by SFCprep-HPLC (Column: CHIRALPAK IG, 20×250 mm, 5 μm; Mobile Phase A:CO₂,Mobile Phase B:IPA (2 mM NH₃-MEOH); Flow rate: 40 mL/min; Gradient: 50%B; 220 nm; RT 1:7.1 min; Injection Volume:2 mL; Number Of Runs: 4) toafford 87-B as an off-white solid (13.3 mg).

To compound 87-A (130 mg, 0.239 mmol) in EA (10 mL) was added Pd/C (100mg). The mixture was stirred for 2 h at rt under H₂. The mixture wasfiltered through a celite pad and washed with EA (20 mL) and CH₃OH (20mL). The filtrate was concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC (XBridge Prep OBD C₁₈ Column,19×250 mm, 5 μm; Mobile Phase A:Water (10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O),Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient:10 B to 30 B in 7min; 220 nm; RT: 6.13 min) to provide 88-A as a white solid (52.5 mg,48%).

6-amino-2-(3,5-dichloro-4-((5-(3,3-dimethylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewas prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione,starting from 3,3-dimethylcyclobutane-1-carboxylic acid.

LCMS Structure (ESI, m/z) ¹H NMR

451[M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.36-12.03 (m, 2H), 7.84-7.85(m, 2H), 7.40-7.50 (m, 1H), 6.52 (s, 2H), 3.60-3.65 (m, 1H), 2.24-2.46(m, 3H), 1.84-2.00(m, 1H), 1.61- 1.75 (m, 1H), 1.19-1.20 (m, 1H),1.01-1.09 (m, 2H). 6-Amino-2-(3,5-dichloro-4-[[5-(3-methylcyclobutyl)-6-oxo-1H- pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione

1^(st) eluting isomer was labelled 86- A. 451 [M + H]⁺ ¹H NMR(300 MHz,DMSO-d₆) δ 12.13-12.27(m, 2H), 7.84 (s, 2H), 7.40-7.41 (m, 1H), 6.52 (s,2H), 3.15-3.25 (m, 1H), 2.29-2.45 (m, 3H), 1.60-1.78 (m, 2H), 0.98 (d, J= 6.0 Hz, 3H). 6-Amino-2-(3,5-dichloro-4-((5-((1r,3r)-3-methylcyclobutyl)-6-oxo- 1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

2^(nd) eluting isomer was labelled 86-B. 451 [M + H]⁺ ¹H NMR (300 MHz,DMSO-d₆) δ 12.14-12.27 (m, 2H), 7.84 (s, 2H), 7.49-7.50 (m, 1H), 6.52(s, 2H), 3.59-3.65 (m, 1H), 2.23-2.38 (m, 3H), 1.88-1.98 (m, 2H), 1.18(d, J = 6.0 Hz, 3H). 6-Amino-2-(3,5-dichloro-4-((5-((1s,3s)-3-methylcyclobutyl)-6-oxo- 1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

543 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.28 (s, 1H), 12.19 (s,1H), 7.84 (s, 2H), 7.44-7.47 (m, 1H), 7.24-7.37 (m, 5H), 6.53 (s, 2H),4.42 (s, 2H), 4.03-4.11 (m, 1H), 2.99-3.06 (m, 1H), 2.53-2.63 (m, 2H),1.93-2.05 (m, 2H). 6-Amino-2-(4-((5-((1r,3r)-3-(benzyloxy)cyclobutyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

543 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 12.10-12.40 (m, 2H), 7.85 (s,2H), 7.58 (s, 1H), 7.24-7.38 (m, 5H), 6.50 (s, 2H), 4.41 (s, 2H), 4.13-4.22 (m, 1H), 3.47-3.57 (m, 1H), 2.28-2.45 (m, 4H).6-Amino-2-(4-((5-((1s,3s)-3- (benzyloxy)cyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione

453 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 12.10-12.42 (m, 2H), 7.85 (s,2H), 7.38-7.41 (m, 1H), 6.51 (s, 2H), 5.09-5.15 (m, 1H), 4.06-4.13 (m,1H), 2.88-2.95 (m, 1H), 2.50-2.60 (m, 2H), 1.85-1.93 (m, 2H). 6-Amino-2-[3,5-dichloro-4-([6-oxo-5- [(1r,3r)-3-hydroxycyclobutyl]-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4- triazine-3,5-dione

465 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 12.15 (s, 1H),7.84 (s, 2H), 7.45(s, 1H), 6.54 (s, 2H),3.34- 3.32 (m, 1H), 2.08-2.06(m, 2H), 2.06-1.93 (m, 2H), 1.24 (s, 3H), 1.10 (s, 3H)6-Amino-2-(3,5-dichloro-4-((5-(3,3- dimethylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione Thefollowing compounds were prepared similarly as described for6-amino-2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione.

463 [M + H]⁺ ¹HNMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.86 (s, 2H),7.54 (s, 1H), 6.46 (s, 2H), 3.72-3.67 (m, 1H), 2.34 (d, J = 8.4 Hz, 4H),0.54- 0.41 (m, 4H). 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(spiro[2.3]hexan-5-yl)-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

477 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 1.78-1.82 (m, 2H), 1.88-1.92(m, 2H), 2.05-2.12 (m, 4H), 2.32 (td, 2H, J = 9.3 Hz, 2.8 Hz), 3.36-3.38(m, 1H), 6.51 (br.s, 2H), 7.4 (d, 1H, J = 1.5 Hz), 7.84 (s, 2H), 12.13(s, 1H), 12.26 (br.s, 1H) 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(spiro[3.3]heptan-2-yl)-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

449 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 12.16 (s, 1H),7.82 (s, 2H), 7.29 (s, 1H), 6.49 (s, 2H), 2.56 (s, 1H), 2.14 (s, 6H)6-amino-2-(4-((5- (bicyclo[1.1.1]pentan-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione

463 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 0.64 (t, J = 5.3 Hz, 2H),0.77(t, J = 5.1 Hz, 2H), 0.80 (d, J = 6.9 Hz, 6H),1.94 (p, J = 6.8 Hz,1H),6.51 (s, 2H), 7.38 (s, 1H), 7.84 (s, 2H), 12.14 (s, 1H), 12.27 (s,br, 1H) 6-amino-2-(3,5-dichloro-4-((5-(1-isopropylcyclopropyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

501 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (s, 2H), 7.48 (s, 1H),6.53 (s, 2H), 2.90 (t, J = 11.6 Hz, 1H), 1.89- 2.11 (m, 6H), 1.62-1.68(m, 2H) 6-amino-2-(3,5-dichloro-4-((5-(4,4-difluorocyclohexyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 1.82-1.91 (m, 1H), 2.03-2.08(m, 1H), 2.85-2.91 (m, 3H), 2.97-3.04 (m, 1H), 3.10-3.18 (m, 1H), 6.51(s, 2H), 7.08-7.16 (m, 4H), 7.47 (s, 1H), 7.86 (s, 2H), 12.27 (br s,1H), 12.29 (s, 1H) 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(1,2,3,4-tetrahydronaphthalen-2-yl)- 1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.11-12.31 (m, 2H), 7.87 (s,2H), 7.71 (s, 1H), 7.32-7.37 (m, 4H), 7.20-7.24 (m, 1H), 6.52 (s, 2H),3.58-3.66 (m, 2H), 3.38-3.49 (m, 2H), 2.53-2.63 (m, 2H)6-amino-2-(3,5-dichloro-4-((6-oxo-5- ((1s,3s)-3-phenylcyclobutyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

513 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.14-12.34 (m, 2H), 7.85 (s,2H), 7.53 (s, 1H), 7.29-7.33 (m, 4H), 7.17-7.23 (m, 1H), 6.54 (s, 2H),3.46-3.58 (m, 2H), 2.63-2.70 (m, 2H), 2.20-2.29 (m, 2H).6-amino-2-(3,5-dichloro-4-((6-oxo-5- ((1r,3r)-3-phenylcyclobutyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

463 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.27 (s, 1H), 12.13 (s,1H), 7.84 (s, 2H), 7.29 (s, 1H), 6.53 (s, 2H), 2.08 (s, 1H), 1.71-1.95(m, 6H), 1.47-1.55 (m, 2H) 6-amino-2-(4-((5-(bicyclo[2.1.1]hexan-1-yl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

467 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.18-12.27 (m, 2H), 7.85-7.86(m, 2H), 7.45-7.46 (m, 1H), 6.53 (s, 2H), 3.85-3.93 (m, 1H), 3.16-3.18(m, 3H), 2.98-3.10 (m, 1H), 2.58- 2.65(m, 2H), 1.90-1.99 (m, 2H)6-amino-2-(3,5-dichloro-4-((5- ((1r,3r)-3-methoxycyclobutyl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

467 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.19-12.27 (m, 2H),7.85-7.86(m, 2H), 7.56-7.57 (m, 1H), 6.52 (s, 2H), 3.96-4.00 (m, 1H),3.49- 3.53(m, 1H), 3.17-3.18 (m, 3H), 2.36-2.42 (m, 2H), 2.24-2.32(m,2H) 6-amino-2-(3,5-dichloro-4-((5- ((1s,3s)-3-methoxycyclobutyl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

462 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.29-12.31 (m, 1H), 7.96 (s,2H), 7.59-7.64 (m, 1H), 5.85 (s, 2H), 3.78-3.97 (m, 2H), 2.56-2.66 (m,1H), 2.10-2.32 (m, 3H) rac-6-amino-2-(3,5-dichloro-4-((5-(2-methylcyclobutyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

462 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 2H), 7.85 (s, 2H),7.59 (d, J = 1.3 Hz, 1H), 6.44 (s, 2H), 3.82- 3.89 (m, 1H), 3.57-3.65(m, 1H), 2.22-2.32 (m, 4H) trans-2-(6-(4-(6-amino-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)- 2,6-dichlorophenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)cyclobutane- 1-carbonitrile

473 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.31-12.28 (m, 2H), 7.85 (s,2H), 7.66 (s, 1H), 6.53 (s, 2H),3.39-3.31 (m, 1H), 2.94-2.86 (m, 4H)6-amino-2-(3,5-dichloro-4-((5-(3,3- difluorocyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

499 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 1.21-1.25 (m, 2H), 1.37-1.43(m, 2H), 6.50 (s, 2H), 7.17-7.27 (m, 1H), 7.26-7.34 (m, 4H), 7.58 (s,1H), 7.84 (s, 2H), 12.17 (s, 1H), 12.26 (br s, 1H) ppm6-amino-2-(3,5-dichloro-4-((6-oxo-5- (1-phenylcyclopropyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

499 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 3.1 (dd, 2H, J = 15.5 Hz, 8.2Hz), 3.25 (dd, 2H, J = 15.5 Hz, 7.8 Hz), 3.72 (quint, 1H, J = 8.2 Hz),6.49 (s, 2H), 7.17 (dd, 2H, J = 5.7 Hz, 3.0 Hz), 7.26 (dd, 2H, J = 5.0Hz, 2.8 Hz), 7.45 (s, 1H), 7.84 (s, 2H), 12.26 (br s, 1H), 12.27 (s, 1H)ppm 6-amino-2-(3,5-dichloro-4-((5-(2,3-dihydro-1H-inden-2-yl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

485 [M + H]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.25-12.33 (m, 2H), 7.82 (s,2H), 7.20-7.40 (m, 5H), 6.52 (s, 2H), 4.71 (s, 1H), 3.63-3.69 (m, 1H),3.19- 3.24 (m, 1H) 6-amino-2-(4-((5-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine- 3,5(2H,4H)-dione

465 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.18-12.28 (m, 2H), 7.85 (s,2H), 7.38 (s, 1H), 6.53 (s, 2H), 3.03-2.90 (m, 1H), 2.55-2.67 (m, 1H),2.02- 2.13 (m, 1H), 1.68-1.93 (m, 4H), 1.53-1.66 (m, 1H), 1.08 (d, J =6.9 Hz, 3H) 6-amino-2-(3,5-dichloro-4-((5-(1-cyclobutylethyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

465 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.18-12.28 (m, 2H), 7.85 (s,2H), 7.38 (s, 1H), 6.53 (s, 2H), 3.03-2.90 (m, 1H), 2.55-2.67 (m, 1H),2.02- 2.13 (m, 1H), 1.68-1.93 (m, 4H), 1.53-1.66 (m, 1H), 1.08 (d, J =6.9 Hz, 3H) 6-amino-2-(3,5-dichloro-4-((5-(1-cyclobutylethyl)-6-oxo-1,6- dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

465 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 2H), 7.87 (s, 2H),7.46 (s, 1H), 6.51 (s, 2H), 2.78-2.87 (m, 1H), 1.92-2.03 (m, 1H), 1.23(d, J = 7.5 Hz, 3H), 0.86 (d, J = 6 Hz, 6H)6-amino-2-(3,5-dichloro-4-((5-(3- methylbutan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

465 [M + H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 2H), 7.87 (s, 2H),7.46 (s, 1H), 6.51 (s, 2H), 2.78-2.87 (m, 1H), 1.92-2.03 (m, 1H), 1.23(d, J = 7.5 Hz, 3H), 0.86 (d, J = 6 Hz, 6H)6-amino-2-(3,5-dichloro-4-((5-(3- methylbutan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

Example 74: Synthesis of Compound 90

Anhydrous THF (5 mL) was added to a mixture of6-bromo-4-isopropylquinolin-2(1H)-one (was prepared as in Synthesis (6),934-942; 2011 and International Journal of Chemical Sciences, 7(3),1784-1792; 2009) (400 mg, 1.50 mmol) and NaH 60% (90 mg) at 0° C., underN₂. The reaction mixture was stirred at 25° C. for 1 h. Then, themixture was cooled to −78° C. and t-BuLi (1.94 mL) was added dropwiseand the reaction mixture was stirred at −78° C. for 30 min. Then, asolution of 2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide(368 mg) in anhydr. THF (5 mL) was added dropwise to the reactionmixture at −78° C. The reaction was further stirred at this temperaturefor 1.5 h and finally hydrolyzed with sat. aq. NH₄Cl (8 mL) and pouredin DCM (50 mL). The organic phase was washed with water (3×), dried overMgSO₄, filtered and evaporated to dryness. The crude mixture waspurified by chromatography on silica gel (20 to 85% EA in cyclohexane)to give2,2,2-trifluoro-N-(4-(hydroxy(4-isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethyl-phenyl)acetamideas a white solid (162 mg, 25%). LCMS (ESI, m z): 433 [M+H]⁺.

Et₃SiH (1.71 mL) and TMSOTf (0.039 mL) were added dropwise to a solutionof2,2,2-trifluoro-N-(4-(hydroxy(4-isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethylphenyl)acetamide(255 mg, 0.59 mmol) in anhydr. DCM (29 mL) at 0° C. under N₂. Thereaction was stirred at 0° C. for 1 h, the ice bath was removed and thereaction was stirred at 25° C. for 6 h. Additional Et₃SiH (0.57 mL) andTMSOTf (0.013 mL) were added and the reaction mixture was stirred at rt.After 16 h, 36 h, and 42 h, additional Et₃SiH (0.57 mL) and TMSOTf(0.013 mL) were added and the mixture was stirred for 64 h. The reactionmixture was evaporated to dryness. NaHCO₃ (sat., aq., 50 mL) and EA(3×50 mL) were added. The combined organic layers were washed with brine(150 mL), dried over MgSO₄, the solids were removed by filtration andthe filtrate was evaporated to dryness to afford2,2,2-trifluoro-N-(4-((4-isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethylphenyl)acetamide(306 mg) which was used without purification in the next step. ¹H NMR(DMSO, 400 MHz) δ 1.19 (d, J=6.8 Hz, 6H), 2.22 (s, 6H), 3.20 (hept.,J=6.8 Hz, 1H), 4.06 (s, 2H), 6.31 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.22(d, J=8.4 Hz, 1H), 7.37 (s, 2H), 7.42 (s, 1H), 11.09 (br s, 1H), 11.52(br s, 1H) ppm. LCMS: C₂₃H₂₃F₃N₂O₂ [M+H]⁺: 417

NaOH (94 mg) was added to a solution of2,2,2-trifluoro-N-(4-((4-isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethylphenyl)acetamide(245 mg, 0.59 mmol) in MeOH (25 mL) and water (2.5 mL) under N₂. Thereaction mixture was stirred at 60° C. for 37 h. Additional NaOH (23 mg)was added and heating continued for 24 h. Then, the reaction mixture wasquenched with water (150 mL). The solution was extracted with EA (3×100mL). The combined organic layers were washed with brine (100 mL), driedover MgSO₄, the solids were removed by filtration and the filtrate wasevaporated to dryness. The crude product was purified by chromatographyon silica gel (MeOH:DCM=0-10%) to give6-(4-amino-2,6-dimethyl-benzyl)-4-isopropylquinolin-2(1H)-one as a whitesolid (133 mg, 71%). ¹H-NMR (DMSO, 400 MHz): 1.19 (d, J=6.8 Hz, 6H),2.06 (s, 6H), 3.17 (hept., J=6.8 Hz, 1H), 3.89 (s, 2H), 4.76 (s, 2H),6.29 (s, 2H), 6.30 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz,1H), 7.37 (s, 2H), 11.50 (br s, 1H) ppm. LCMS: C₂₁H₂₄N₂O [M+H]⁺: 321

2-(4-((4-Isopropyl-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,compound 90, was prepared similarly as described for2-(4-[[3-isopropyl-1-(4-methylbenzene-sulfonyl)indol-5-yl]oxy]-3,5-dimethylphenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile,starting from6-(4-amino-2,6-dimethylbenzyl)-4-isopropylquinolin-2(1H)-one.

Example 75: Synthesis of Compound 91 and 91-A

Water (17 mL) was added to a solution of(5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (1 eq., 0.95 g, 5.4mmol), 4-bromo-6-chloropyridazin-3-amine (1.12 g, 5.4 mmol), Na₂CO₃(1.14 g, 10.8 mmol) and Pd(dppf)Cl₂ DCM (0.37 g, 0.46 mmol) in1,4-dioxane (51 mL). The reaction mixture was evacuated and backfilledwith N₂ (3×) and was stirred at 110° C. for 1 h. After cooling to rt,the reaction mixture was diluted in EA and washed with brine. Theaqueous phase was extracted with EA (2×). The combined organic phaseswere dried with Na₂SO₄, filtered and evaporated to dryness. The crudemixture was purified by flash chromatography on silica gel (0% to 10%CH₃OH in DCM) to give6-chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazin-3-amine (1.12 g,80%) as a beige solid. ¹H-NMR (300 MHz DMSO-d₆,) δ 1.75-1.76 (m, 4H),2.76-2.77 (m, 4H), 6.32 (br s, 2H), 7.20-7.23 (m, 3H), 7.30 (s, 1H) ppm.

t-Butyl nitrite (1.05 mL, 8.78 mmol) was added to a solution of6-chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazin-3-amine (1.14 g,4.39 mmol) and CuCl (0.87 g, 8.78 mmol) in anhydrous CH₃CN (40 mL) underN₂. The reaction mixture was stirred at 60° C. for 24 h. After coolingto rt, the reaction mixture was diluted in EA, washed with sat. aq.NaHCO₃(2×), washed with brine, dried over MgSO₄, filtered and evaporatedto dryness. The crude mixture was purified by flash chromatography onsilica gel (0% to 3% CH₃OH in DCM) to give3,6-dichloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazine (0.81 g,66%) as a yellow solid. ¹H-NMR (300 MHz DMSO-d₆,) δ 1.77 (m, 4H), 2.78(m, 4H), 7.21-7.35 (m, 3H), 8.06 (s, 1H) ppm.

Preparation of2-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione

A cooled solution of NaNO₂ (3.88 g, 56.2 mmol) in water (6.5 mL) wasadded to a solution of 4-amino-2,6-dichlorophenol (10 g, 56.2 mmol) inHCl 37% (23 mL, 281 mmol) and water (63 mL) at 0° C. under N₂. Thereaction mixture was stirred at 0° C. for 1 h. This reaction mixture wasslowly added to a mixture of ethyl N-(2-cyanoacetyl)carbamate (10.5 g,67.4 mmol), ice (20 g), water (25 mL) and pyridine (225 mL) at 0° C. Theresulting reaction mixture was stirred at 0° C. for 1 h. The precipitatewas filtered and washed with water. The precipitate was dissolved in DCMand CH₃OH and evaporated to dryness to give ethyl(2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazineylidene)acetyl)carbamate(11.94 g, 62%) as a yellow solid, that was used without furtherpurification in the next step.

NaOAc (4 eq., 11.35 g, 0.14 mol) was added to a solution of ethyl(2-cyano-2-(2-(3,5-dichloro-4-hydroxyphenyl)hydrazineylidene)acetyl)carbamate(11.94 g, 35 mmol) in acetic acid (330 mL) under N₂. The reactionmixture was heated to reflux for 3 h and then cooled to 0° C., water(400 mL) was added and the mixture was stirred for 2 h. Then, theprecipitate was filtered, washed with water, dissolved in CH₃OH andevaporated to dryness to give2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(6.48 g, 63%) as a beige solid that was used without furtherpurification in the next step.

A mixture of2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(1 eq., 6.48 g, 21.7 mmol), HCl 37% (16 mL, 195 mmol) and AcOH (33 mL,580 mmol) under N₂ was stirred at 120° C. for 2.5 h. After cooling tort, the reaction mixture was diluted in water and the precipitate wasfiltered and washed with water. The precipitate was dissolved in CH₃OHand evaporated to dryness to give2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (9.2 g) as a yellow solid, that was used without furtherpurification in the next step. ¹H-NMR (400 MHz DMSO-d₆,) δ 7.57 (s, 2H),10.66 (s, 1H), 12.57 (br s, 1H) ppm.

A solution of2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (8.88 g, 27.9 mmol) in mercaptoacetic acid (14 mL) under N₂ wasstirred at 170° C. for 3 h. After cooling to rt, the reaction mixturewas diluted in water and the precipitate was filtered and washed withwater. The precipitate was dissolved in CH₃OH and evaporated to drynessto give 2-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione(9.4 g) as a yellow solid, that was used without further purification inthe next step. ¹H-NMR (DMSO, 300 MHz): 4.37 (s, 1H), 7.54 (s, 2H), 7.61(s, 1H) ppm.

A mixture of3,6-dichloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazine (780 mg,2.79 mmol),2-(3,5-dichloro-4-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (766mg, 2.79 mmol), K₂CO₃ (1.16 mg, 8.38 mmol) and CuI (266 mg, 1.4 mmol) inanhydrous DMSO (13 mL) under N₂ was stirred at 120° C. for 16 h. Aftercooling to rt, the reaction mixture was diluted in EtOAc and washed withsat. aq. NH₄Cl (2×). The aqueous phase was extracted with EtOAc (2×) andthe combined organic layers were dried over Na₂SO₄, filtered andevaporated to dryness. The crude mixture was purified by flashchromatography on silica gel (0% to 3% MeOH in DCM) to give a mixture of2-(3,5-dichloro-4-((6-chloro-5-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneand2-(3,5-dichloro-4-((6-chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(65:35, 593 mg, 41%) as a beige solid. LCMS: C₂₃H₁₆C₁₃N₅O₃ [M+H]⁺:516/518.

The regioisomeric compound mixture (560 mg, 1.08 mmol) and NaOAc (533mg, 6.50 mmol) in AcOH (11 mL) under N₂ was stirred at 118° C. for 4 h.After cooling to rt, the reaction mixture was diluted in water,filtered, washed with water (3×) and n-pentane. The precipitate wasdissolved in EtOAc, dried with Na₂SO₄, filtered and evaporated todryness. The crude mixture was purified by flash chromatography onsilica gel (0% to 5% MeOH in DCM) to give two fractions. The firstfraction was purified by trituration with diethylether (3×) to give2-(3,5-dichloro-4-((6-oxo-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(286 mg, 53%) as a beige solid. ¹H-NMR (400 MHz DMSO-d₆,) δ 1.76 (br s,4H), 2.77 (br s, 4H), 7.15-7.17 (m, 1H), 7.68-7.71 (m, 3H), 7.82 (s,3H), 12.41 (s, 1H), 12.49 (br s, 1H) ppm. LCMS: C₂₃H₁₆C₁₃N₅O₃ [M+H]⁺:516/518.

The second fraction was purified by trituration with Et₂O (3×) to give2-(3,5-dichloro-4-((6-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(64 mg, 12%) as a beige solid. ¹H-NMR (400 MHz DMSO-d₆,) δ 1.77 (br s,4H), 2.78 (br s, 4H), 7.06 (d, J=2.4 Hz, 1H), 7.22 (d, J=7.9 Hz, 1H),7.48-7.52 (m, 2H), 7.70 (s, 1H), 7.81 (s, 2H), 12.34 (d, J=2.5 Hz, 1H),12.49 (br s, 1H) ppm. LCMS: C₂₃H₁₆C₁₃N₅O₃: [M+H]⁺: 516/518.

Example 76: Synthesis of Compounds 92 and 92-A

The titled compounds were prepared using a method analogous to thatdescribed for2-(3,5-dichloro-4-((6-oxo-5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneand2-(3,5-dichloro-4-((6-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewith the exception that 2-naphthylboronic acid was employed in the arylcoupling reaction instead of (5,6,7,8-tetrahydronaphthalen-2-yl)boronicacid.

92: ¹H-NMR (400 MHz DMSO-d₆,) δ 7.56-7.64 (m, 2H), 7.72 (s, 1H), 7.84(s, 2H), 7.96-8.07 (m, 5H), 8.68 (s, 1H), 12.51 (s, 1H), 12.55 (s, 1H)ppm. LCMS: C₂₃H₁₃Cl₂N₅O₄ [M+H]⁺: 494/496.

92-A: ¹H-NMR (400 MHz DMSO-d₆,) δ 7.27 (d, J=2.1 Hz, 1H), 7.59-7.67 (m,2H), 7.70 (s, 1H), 7.82 (s, 2H), 7.92 (dd, J=8.5 Hz, 1.9 Hz, 1H),7.99-8.06 (m, 2H), 8.09 (d, J=8.7 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 12.45(d, J=1.9 Hz, 1H), 12.49 (s, 1H) ppm. LCMS: C₂₃H₁₃Cl₂N₅O₄ [M+H]⁺:494/496.

The following compounds were prepared similarly as described for6-amino-2-(3,5-dichloro-4-[[5-(naphthalen-2-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(compound 67).

LC MS Structure (ESI, m/z) NMR

[M + H]⁺ = 511 ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (Br,2H), 9.39(d, J =3.0 Hz, 1H), 8.71(s, 1H), 8.49-8.46(m, 1H), 8.42- 8.38(m, 1H), 8.32-8.21(m, 1H), 8.07 (s,1H), 7.92(s, 2H), 5.79 (Br, 2H)6-amino-2-(3,5-dichloro-4-((5-(cinnolin-6-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 511 ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (Br,1H), 12.30(s, 1H),9.49(d, J = 3.0 Hz, 1H), 8.64 (d, J = 4.4 Hz, 1H),8.52(s,1H),8.35-8.31(m, 2H), 7.91(s, 2H), 7.37(s, 1H), 6.33 (Br,2H)6-amino-2-(3,5-dichloro-4-((4-(cinnolin-6-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 511 ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (Br,1H), 9.45(d, J =3.0 Hz, 1H), 9.21(s, 1H), 8.39-8.37(m, 1H), 8.37- 8.36(m, 1H), 8.28(s,1H), 8.23-8.17(m, 1H), 7.96(s,2H), 6.10 (Br,2H)6-amino-2-(3,5-dichloro-4-((5-(cinnolin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 511 ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (Br,2H), 9.48(d, J =3.0 Hz, 1H), 8.91(s, 1H), 8.34-8.32(m, 1H), 8.29- 8.25(m, 2H), 7.94(s,2H), 7.43(s, 1H), 6.18 (Br,2H)6-amino-2-(3,5-dichloro-4-((4-(cinnolin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 487 ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 12.28 (s, 1H),7.72- 7.87 (m, 5H), 7.77 (d, J = 7.8 Hz, 1H), 6.53 (s, 2H), 2.29 (s, 6H)6-amino-2-(3,5-dichloro-4-((5-(3,4-dimethylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 487 ¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 12.27 (s, 1H),7.86 (s, 2H), 7.51-7.57 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.06 (s, 1H),6.51 (s, 2H), 2.29 (s, 6H) 6-amino-2-(3,5-dichloro-4-((4-(3,4-dimethylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 515 ¹H NMR (400 MHz, DMSO-d₆) δ 12.37 C 12.29 (m, 2H), 7.86 C7.78 (m, 5H), 6.83C 6.81 (m, 1H),6.55 (s, 2H), 4.21 C 4.19 (m, 2H), 2.82C 2.78 (m, 2H), 1.98C 1.95 (m, 6H)6-amino-2-(3,5-dichloro-4-((5-(chroman-6-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 515 ¹H NMR (400 MHz, DMSO-d₆) δ 12.92 (s, 2H), 7.86 (s, 2H),7.56 C 7.54 (m, 2H), 7.03 (s, 1H), 6.90C 6.88 (m, 1H), 6.54 (s, 2H),4.21 C 4.19 (m, 2H), 2.83 C 2.80 (m, 2H), 1.97C 1.94 (m, 2H)6-amino-2-(3,5-dichloro-4-((4-(chroman-6-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 507 ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (br, 1H), 12.27 (br,1H), 7.87- 8.06 (m, 5H), 7.53 (d, J = 8.1 Hz, 1H), 6.53 (s, 2H), 2.40(s, 3H). 6-amino-2-(3,5-dichloro-4-((5-(4-chloro-3-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 507 ¹HNMR (400 MHz, DMSO-d₆) δ 12.28- 12.41 (m, 2H), 7.87 (s,2H), 7.78 (s, 1H), 7.59- 7.67 (m, 2H), 7.16 (s, 1H), 6.54 (s, 2H), 2.41(s, 3H) 6-amino-2-(3,5-dichloro-4-((4-(4-chloro-3-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 525 ¹HNMR (400 MHz, DMSO-d₆) δ 12.29- 12.57 (m, 2H), 7.99 (s,1H), 7.82-7.90 (m, 4H), 7.53-7.60 (m, 1H), 7.23- 7.40 (m, 2H), 6.55 (s,2H) 6-amino-2- (3,5-dichloro-4-((5-(3-difluoromethoxyphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 525 ¹H NMR (400 MHz, DMSO-d₆) δ 12.28- 12.46 (m, 2H), 7.87(s, 2H), 7.59 C 7.72 (m, 3H), 7.36-7.39 (m, 2H), 7.21-7.23 (m, 1H), 6.55(s, 2H) 6-amino-2-(3,5-dichloro-4-((4-(3-(difluoromethoxy)phenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 525 ¹H NMR (400 MHz, DMSO-d₆) δ 12.27- 12.40 (m, 2H), 7.72-7.87 (m, 5H), 7.33 (d, J = 8.1 Hz, 1H), 6.53 (s, 2H), 2.50 (t, J = 1.8Hz, 4H), 2.01-2.11 (m, 2H)6-amino-2-(3,5-dichloro-4-((5-(2,3-dihydro-1H-inden-5-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 525 ¹H NMR (400 MHz, DMSO-d₆) δ 12.26- 12.33 (m, 2H), 7.86(s, 2H), 7.63 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz,1H), 7.05 (s, 1H), 6.53 (s, 2H), 2.91-2.96 (m, 4H), 2.01- 2.11 (m, 2H)6-amino-2-(3,5-dichloro-4-((4-(2,3-dihydro-1H-inden-5-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 12.29 (s, 1H),9.84 (s, 1H), 8.09-8.18 (m, 2H), 7.76-7.89 (m, 4H), 6.66-6.71 (m, 1H),6.53 (s, 2H) 6-amino-2-(3,5-dichloro-4-((6-oxo-5-(pyrazolo[1,5-a]pyridin-6-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (400 MHz, DMSO-d₆) δ 12.44 (s, 1H), 12.28 (s, 1H),9.17 (s, 1H), 8.11-8.15 (m, 1H), 7.82-7.89 (m, 3H), 7.57-7.62 (m, 1H),7.35 (s, 1H), 6.70-6.74 (m, 1H), 6.54 (s, 2H)6-amino-2-(3,5-dichloro-4-((6-oxo-4- (pyrazolo[1,5-a]pyridin-6-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (300 MHz, DMSO-d₆) δ 12.60 (s, 1H), 12.28 (s, 1H),8.70- 8.77 (m, 2H), 8.08-8.11 (m, 2H), 7.88 (s, 2H), 7.46-7.49 (m, 1H),6.82 (d, J = 1.8 Hz. 1H), 6.54 (br, 2H)6-amino-2-(3,5-dichloro-4-((6-oxo-5- (pyrazolo[1,5-a]pyridin-5-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (d, J = 7.2 Hz, 1H),8.11-8.18 (m, 2H), 7.98 (s, 2H), 8.27-7.28 (m, 2H), 6.82 (d, J = 1.5 Hz.1H), 5.87 (br, 2H) 6-amino-2-(3,5-dichloro-4-((6-oxo-4-(pyrazolo[1,5-a]pyridin-5-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (300 MHz, DMSO-d₆) δ 12.52 (s, 1H), 8.80 C 8.81(m, 1H), 8.39 C 8.47 (m, 2H), 8.01 (s, 1H), 7.87 (s, 2H), 7.62 (s, 1H),7.25 C 7.29 (m, 1H), 6.47 (s, 2H).6-amino-2-(3,5-dichloro-4-((5-(imidazo[1,5-a]pyridin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (300 MHz, DMSO-d₆) δ 12.25 C 12.38 (m, 2H), 8.42 C8.53 (m, 2H), 8.11 (s, 1H), 7.88 (s, 2H), 7.59 (s, 1H), 7.23 (s, 1H),7.03 C 7.07 (m, 1H), 6.49 (s, 2H)6-amino-2-(3,5-dichloro-4-((4-(imidazo[1,5-a]pyridin-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 510 ¹H NMR (300 MHz, DMSO-d₆) δ 12.52 (br, 1H), 8.97-8.94 (m,1H), 8.72-8.71 (m, 1H), 8.51-8.47 (m, 1H), 8.28 (d, J = 1 Hz, 1H),8.05-8.02 (m, 4H), 7.62-7.60(m, 1H),5.65(s, 2H)6-amino-2-(3,5-dichloro-4-((6-oxo-5-(quinolin-6-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 510 ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 C 8.99 (m, 1H), 8.49 (d,J = 4.0 Hz, 1H), 8.43 (s, 1H), 8.17 (s,2H), 8.01 (s, 2H), 7.65-7.62 (m,1H), 7.22 (s, 1H), 5.56(s, 2H).6-amino-2-(3,5-dichloro-4-((6-oxo-4-(quinolin-6-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (400 MHz, DMSO-d₆) δ 12.78- 11.75 (m, 2H), 8.79 C8.72 (m, 1H), 8.07 (s, 1H), 7.92 C 7.74 (m, 3H), 7.62 (d, J = 0.9 Hz,1H), 7.27-7.15(m, 1H), 7.03-6.95 (m, 1H), 6.49 (s, 2H)6-amino-2-(3,5-dichloro-4-((6-oxo-5- (pyrazolo[1,5-a]pyridin-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 499 ¹H NMR (400 MHz, DMSO-d₆) δ 8.84-8.82 (m, 1H), 7.89 (s,2H), 7.83 (m, 1H), 7.52 (s, 1H), 7.35 (d, J = 0.9 Hz, 1H), 7.34-7.32 (m,1H), 7.08-7.03 (m, 1H), 6.49 (s, 2H).6-amino-2-(3,5-dichloro-4-((6-oxo-4- (pyrazolo[1,5-a]pyridin-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4- triazine-3,5(2H,4H)-dione

[M + H]⁺ = 510 ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 9.04 (d, J =2.0 Hz, 1h), 8.19 (s, 1H), 8.08- 8.11 (m, 2H), 7.93 (s, 2H), 7.84-7.88(m, 1H), 7.68-7.71 (m, 1H), 6.32 (s, 2H).6-amino-2-(3,5-dichloro-4-((6-oxo-5-(quinolin-3-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 510 ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (br, 2H), 9.28 (d, J =2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.8 Hz, 2H),7.89-7.92 (m, 3H), 7.71-7.75 (m, 1H), 7.43 (s, 1H), 6.51 (s, 2H).6-amino-2-(3,5-dichloro-4-((6-oxo-4-(quinolin-3-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 510 ¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.66 (s, 1H),8.26 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.80- 7.93 (m, 4H),7.62 (s, 1H), 6.33 (br, 2H).6-amino-2-(3,5-dichloro-4-((4-(isoquinolin-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneThe following compounds were prepared similarly as described forcompounds 91 and 91-A.

LCMS Structure (ESI, m/z) ¹HNMR

[M + H]⁺ = 500 ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (d, 1H, J = 5.4 Hz),7.71 (s, 1H), 7.83-7.86 (m, 3H), 7.93 (dd, 1H, J = 8.6 Hz, 1.8 Hz), 7.98(s, 1H), 8.12 (d, 1H, J = 8.5 Hz), 8.59 (d, 1H, J = 1.8 Hz), 12.50-12.52(m, 2H) 2-(4-((5-(benzo[b]thiophen-5-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 500 ¹H NMR (400 MHz, DMSO-d₆) δ 7.21 (d, 1H, J = 2.1 Hz),7.58 (d, 1H, J = 5.5 Hz), 7.70 (br.s, 1 H), 7.77 (dd, 1H, J = 8.6 Hz,1.9 Hz), 7.82 (s, 2H), 7.9 (d, 1H, J = 5.5 Hz), 8.2 (d, 1H, J = 8.7 Hz),8.31 (d, 1H, J = 1.6 Hz), 12.41 (br.s, 1H), 12.49 (br.s, 1H)2-(4-((4-(benzo[b]thiophen-5-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5- dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 459 ¹H NMR (400 MHz, DMSO-d₆) δ 2.37 (s, 3H), 7.59 (br s,1H), 7.82 (s, 2H), 8.02 (s, 1H), 8.17-8.19 (m, 1H), 8.51 (d, J = 1.7 Hz,1H), 8.91 (d, J = 1.9 Hz, 1H), 12.50 (br s, 1H), 12.57 (s, 1H)2-(3,5-dichloro-4-((5-(5-methylpyridin-3-yl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 459 ¹H NMR (400 MHz, DMSO-d₆) δ 2.40 (s, 3H), 7.27 (d, J =2.0 Hz, 1H), 7.66 (s, 1H), 7.82 (s, 2H), 8.00- 8.04 (m, 1H), 8.57 (d, J= 1.5 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 12.46 (d, J = 1.6 Hz, 1H),12.49 (s, 1H) 2-(3,5-dichloro-4-((4-(5-methylpyridin-3-yl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 458 ¹H NMR (400 MHz, DMSO-d₆) δ 2.38 (s, 3H), 7.31 (d, 1H, J= 7.6 Hz), 7.38 (t, 1H, J = 7.6 Hz), 7.71 (s, 1 H), 7.75-7.78 (m, 2H),7.82 (s, 2H), 7.86 (s, 1H), 12.47 (s, 1H), 12.50 (br.s, 1H)2-(3,5-dichloro-4-((6-oxo-5-(m-tolyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 458 ¹H NMR (400 MHz, DMSO-d₆) δ 2.38 (s, 3H), 7.1 (d, 1H, J =2.2 Hz), 7.36 (d, 1H, J = 7.6 Hz), 7.44 (t, 1H, J = 7.7 Hz), 7.59-7.61(m, 2H), 7.70 (s, 1H), 7.81 (s, 2H), 12.38 (br.s, 1H), 12.49 (br.s, 1H)2-(3,5-dichloro-4-((6-oxo-4-(m-tolyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)- 1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 459 ¹H NMR (400 MHz, DMSO-d₆) δ 2.55 (s, 3H), 7.72 (d, 1H, J= 1.8 Hz), 7.75 (dd, 1H, J = 5.0 Hz, J = 1.8 Hz), 7.82 (br.s, 1H), 7.83(s, 2H), 8.07 (s, 1H), 8.57 (d, 1H, J = 5.3 Hz), 12.50 (br.s, 1H), 12.63(s, 1H). 2-(3,5-dichloro-4-((5-(2-methylpyridin-4-yl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[M + H]⁺ = 459 ¹H NMR (400 MHz, DMSO-d₆) δ 2.62 (s, 3H), 7.32 (s, 1H),7.71 (d, 1H, J = 1.8 Hz), 7.73 (dd, 1 H, J = 5.2 Hz, J = 1.8 Hz), 7.79(br.s, 1H), 7.82 (s, 2H), 8.72 (d, 1H, J = 5.4 Hz), 12.49 (s, 1H), 12.56(br.s, 1H). 2-(3,5-dichloro-4-((4-(2-methylpyridin-4-yl)-6-oxo-1,6-dihydropyridazin-3- yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

Example 77: Synthesis of Compound 143

The titled compound was prepared similarly as described for compound 82with the exception that 5′-bromospiro[cyclopropane-1,3′-indolin]-2′-onewas used instead of 5-bromo-3,3-dimethylindolin-2-one. ¹H NMR (400 MHz,DMSO-d₆) δ 1.44-1.48 (m, 2H), 1.55-1.60 (m, 2H), 6.43 (dd, J=8.4 Hz, 2.6Hz, 1H), 6.49 (brs, 2H), 6.75 (d, J=2.6 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H),7.89 (s, 2H), 10.47 (s, 1H), 12.26 (brs, 1H).

Example 78: Synthesis of Compound 144

A 500 mL round-bottom flask was charged with2,2,6,6-tetramethylpiperidine (26 mL) in THF (100 mL) under N₂.n-Butyllithium (60.00 mL, 636.953 mmol) was added dropwise at −78° C.The mixture was warm to −45° C. and stirred for 30 min. Then the mixturewas cooled to −78° C. and 3,6-dichloropyridazine (10.00 g, 67.128 mmol)in THF (100 mL) was added dropwise. The mixture was stirred for 30 minat −78° C. Cyclopentanone (60 mL) in THF (50 mL) was added dropwise. Thereaction was stirred for 60 min at −75° C. The reaction was quenched bysaturated ammonium chloride (100 mL) and extracted with EA (3×100 mL),the combined organic layers were washed with brine (2×100 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith EA/PE (2/5) to afford1-(3,6-dichloropyridazin-4-yl)cyclopentan-1-ol (5 g, 28.76%) as yellowoil. LCMS (ESI, m z): 233 [M+H]⁺.

A 100 mL round-bottom flask was charged with1-(3,6-dichloropyridazin-4-yl)cyclopentan-1-ol (4.50 g, 19.306 mmol) inCH₂Cl₂ (50 mL) under N₂. Bis(2-methoxyethyl)aminosulfur trifluoride(BAST) (12.81 g, 57.918 mmol, 3.00 equiv) was added dropwise at 0° C.The reaction was stirred for 16 h at rt. The reaction mixture wasdiluted with water (50 mL) and filtered through celite, the celite padwas washed with dichloromethane (2×50 mL), the filtrate was washed withbrine (2×50 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column with PE/EA=5/2 to provide the3,6-dichloro-4-(1-fluorocyclopentyl)pyridazine (2.5 g, 44%) as a yellowoil. LCMS (ESI, m z): 235 [M+H]⁺.

To a solution of 3,6-dichloro-4-(1-fluorocyclopentyl) pyridazine (500.00mg, 2.127 mmol), t-butylN-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(827.78 mg, 2.127 mmol) and K₂CO₃ (881.86 mg, 6.381 mmol, 3.00 equiv) inDMSO (10 mL) was added CuI (81.01 mg, 0.425 mmol) under nitrogen. Themixture was stirred for 16 h at 110° C. and then quenched with water (20mL). The mixture was acidified to pH ˜5 with HCl (1M, aq.). Theresulting mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (2×20 mL), dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography, eluted with EA/PE (1:1) to afford6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(1-fluorocyclopentyl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(250 mg, 24%) as a yellow solid. LCMS (ESI, m z): 487 [M+H]⁺.

To a solution of6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(1-fluorocyclopentyl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(200.00 mg, 0.410 mmol) in acetic acid (5 mL) was added sodium acetate(168.21 mg, 2.050 mmol). The mixture was stirred overnight at 100° C.The mixture reaction was cooled to rt and then quenched with water (10ml) and then stirred for 10 min, the resulting solid was filtered andwashed with water (2×10 ml) and petroleum ether (2×5 mL), then driedunder high vacuum to afford the crude product. The crude product (100mg) was purified by preparative HPLC using the following gradientconditions: Column: XBridge Prep OBD C18 Column, 19×250 mm, Sum; mobilePhase A:Water (10 MMOL/L NH₄HCO₃+0.1% NH₃.H₂O), Mobile Phase B: CH₃CN;Flow rate:25 mL/min; Gradient:29 B to 49 B in 7 min; 220 nm; RT1:6.98;Purification resulted in6-amino-2-(3,5-dichloro-4-[[5-(1-fluorocyclopentyl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(4 mg, 2.06%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s,1H), 12.27 (s, 1H), 7.87 (s, 2H), 7.53 (s, 1H), 6.50 (s, 2H), 2.50-2.49(m, 2H), 1.87-1.85 (m, 6H).

Example 79: Synthesis of Compound 145

A mixture of 2-bromo-5-hydroxybenzonitrile (5 g, 25.25 mmol),1,2,3-trichloro-5-nitrobenzene (5.72 g, 25.25 mmol) and K₂CO₃ (5.23 g,37.88 mmol) in DMF (185 mL) under N₂ was stirred at 60° C. for 1 h.After cooling to rt, the reaction mixture was diluted in water andfiltered. The precipitate was washed with water and dissolved in DCM.The solution was dried with MgSO₄, filtered and evaporated to drynessproviding 2-bromo-5-(2,6-dichloro-4-nitrophenoxy)benzonitrile (9.65 g,98%) as a yellow solid which was used without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 7.36 (dd, J=8.9 Hz, 3.1 Hz, 1H), 7.71 (d, J=3.2Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 8.58 (s, 2H) ppm.

A solution of benzophenone hydrazone (1.89 g, 9.64 mmol), Pd(OAc)₂ (98mg, 0.44 mmol) and BINAP (300.1 mg, 0.48 mmol) in toluene (17 mL) wasevacuated and backfilled with N₂ (3×) and the reaction mixture washeated at 100° C. for 3 min. After cooling to rt,2-bromo-5-(2,6-dichloro-4-nitrophenoxy)benzonitrile (3.4 g, 8.76 mmol),Cs₂CO₃ (4 g, 12.27 mmol) and toluene (5.1 mL) were added. The reactionvessel was again evacuated and backfilled with N₂ (3×) and the reactionmixture was heated at 100° C. for 5 h. After cooling to rt, the mixturewas filtrated through a pad of Celite, the Celite was washed with DCM,and the solution was evaporated to dryness providing5-(2,6-dichloro-4-nitrophenoxy)-2-(2-(diphenylmethylene)hydrazinyl)benzonitrile as a dark red solid (4.41 g, quant.) which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 6.76 (d, J=2.9 Hz,1H), 7.15 (dd, J=9.3 Hz, 2.9 Hz, 1H), 7.32-7.37 (m, 6H), 7.59-7.63 (m,4H), 7.73 (d, J=9.3 Hz, 1H), 8.08 (s, 1H), 8.31 (s, 2H) ppm.

p-Toluenesulfonic acid monohydrate (3.33 g, 17.5 mmol) was added to asolution of5-(2,6-dichloro-4-nitrophenoxy)-2-(2-(diphenylmethylene)hydrazineyl)benzonitrile(4.4 g, 8.74 mmol) in MeOH (61 mL) under N₂. The reaction mixture wasrefluxed for 21 h. After cooling to rt, the reaction mixture was dilutedwith a sat. aq. Na₂CO₃ and extracted with EA (3×). The combined organiclayers were washed with brine (3×) and water, dried over MgSO₄, filteredand evaporated to dryness. The crude was purified by chromatography onsilica gel (20% to 70% EA in DCM) providing5-(2,6-dichloro-4-nitrophenoxy)-1H-indazol-3-amine (1.45 g, 49%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.20 (s, 2H), 6.99 (d, J=2.4Hz, 1H), 7.08 (dd, J=9.0 Hz, 2.4 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 8.57(s, 2H), 11.40 (s, 1H) ppm.

Trifluoroacetic anhydride (0.36 mL, 2.57 mmol) was added to a solutionof 5-(2,6-dichloro-4-nitrophenoxy)-1H-indazol-3-amine (435 mg, 1.28mmol) in anhydrous DCM (10 mL) at 0° C. under N₂. The reaction mixturewas stirred at rt for 1 h. Afterward, the reaction mixture was dilutedin water and extracted with DCM (3×). The combined organic layers weredried over MgSO₄, the solids were removed by filtration and the solventof the filtrate was evaporated to dryness. The crude mixture waspurified by flash chromatography on silica gel (20% to 60% EA incyclohexane) to giveN-(5-(2,6-dichloro-4-nitrophenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(558 mg, quant.) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.05 (d,J=2.1 Hz, 1H), 7.17 (dd, J=9.1 Hz, 2.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H),8.56 (s, 2H), 11.82 (s, 1H), 13.18 (s, 1H) ppm.

A solution of NH₄C₁ (685.9 mg, 12.82 mmol) in water (6.4 mL) was addedto a solution ofN-(5-(2,6-dichloro-4-nitrophenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(558 mg, 1.28 mmol) in ethanol (13 mL) under N₂. Fe (358.1 mg, 6.41mmol) was added and the reaction mixture was stirred at 70° C. for 3 h.After cooling to rt, HCl 37% (1 mL) was added and the reaction mixturewas diluted in water. K₂CO₃ was slowly added until basic pH and theresulting solution was extracted with EA (3×). The combined organiclayers were dried with Na₂SO₄, filtered and evaporated to drynessprovidingN-(5-(4-amino-2,6-dichlorophenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(365 mg, 70%) as a green solid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 5.60 (s, 2H), 6.73 (s, 2H),6.85 (s, 1H), 7.08 (d, J=9.1 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 11.74 (s,1H), 13.01 (s, 1H) ppm.

A solution of NaNO₂ (94.8 mg, 1.37 mmol) in water (13.7 mL) was added toa solution ofN-(5-(4-amino-2,6-dichlorophenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(265 mg, 0.65 mmol) in HCl 37% (5.7 mL, 69.1 mmol), acetic acid (17.5mL) and water (13.7 mL) at 0° C. under N₂. The reaction mixture wasstirred at 0° C. for 1 h. In parallel, a solution of ethylN-(2-cyanoacetyl)carbamate (153.2 mg, 0.98 mmol) in water (16.5 mL) andpyridine (5.7 mL) was stirred at 0° C. for 15 min. The first reactionmixture was quickly added to the second one. The resulting reactionmixture was stirred at 0° C. for 1.5 h. Afterwards, the reaction mixturewas diluted in water and filtered. The precipitate was washed with waterproviding ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-(2,2,2-trifluoroacetamido)-1H-indazol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(170 mg, 45%) as a beige solid which was used without furtherpurification.

Sodium acetate (97.5 mg, 1.19 mmol) was added to a solution of ethyl(2-cyano-2-(2-(3,5-dichloro-4-((3-(2,2,2-trifluoroacetamido)-1H-indazol-5-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(170 mg, 0.3 mmol) in acetic acid (10 mL) under N₂. The reaction mixturewas stirred at 120° C. for 3 h. After cooling to 0° C., the reactionmixture was diluted in water, stirred for 30 min at 0° C. and filtered.The precipitate was washed with water and pentane. The crude mixture waspurified by flash chromatography on silica gel (0% to 10% MeOH in DCM)to giveN-(5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(45 mg, 29%) as an orange solid. LCMS: C₁₉H₈Cl₂F₃N₇O₄ [M+H]⁺: 525.

A solution ofN-(5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-1H-indazol-3-yl)-2,2,2-trifluoroacetamide(158 mg, 0.3 mmol) in ammonia (15 mL, 7 N in MeOH) under N₂ was stirredat 60° C. for 3 h. The reaction mixture was evaporated to dryness togive2-(4-((3-amino-1H-indazol-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(127 mg, 98%) as an orange solid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 5.25 (br s, 2H), 6.96 (d,J=2.6 Hz, 1H), 7.05 (dd, J=9.2 Hz, 2.6 Hz, 1H), 7.09 (br s, 1H), 7.24(d, J=8.9 Hz, 1H), 7.81 (s, 2H), 11.34 (br s, 1H) ppm.

Acetone (0.109 mL, 1.48 mmol) was added to a solution of2-(4-((3-amino-1H-indazol-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(127 mg, 0.3 mmol) in ethanol (1.5 mL), THF (1.5 mL) and acetic acid(0.3 mL) under N₂. After cooling to 0° C., NaCNBH₃ (2 eq., 37.1 mg, 0.59mmol) was added and the mixture was stirred at 0° C. for 1.5 h. Then,the reaction mixture was diluted in water and filtered. The precipitatewas washed with water. The crude mixture was purified by flashchromatography on silica gel (0% to 10% MeOH in DCM) and the resultingproduct was dissolved in MTBE and filtered. The solution was evaporatedto dryness to give2-(3,5-dichloro-4-((3-(isopropylamino)-1H-indazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(12 mg, 9%) as a red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.17 (d, J=6.4Hz, 6H), 3.76 (br s, 1H), 5.67 (s, 1H), 6.98 (d, J=2.5 Hz, 1H), 7.09(dd, J=2.5 Hz, 8.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 7.81 (s, 2H), 11.34(s, 1H), 13.28 (br s, 1H).

Example 80: Synthesis of Compound 146 and 147

The mixture of 4-amino-2,6-dichloro-phenol (30 g, 168.52 mmol) and Boc₂O(91.95 g, 421.31 mmol, 96.79 mL) in THF (400 mL) was heated to 80° C.for 2 h. The mixture was concentrated to afford crude. The residue waspurified by silica gel chromatography (eluent of 0-15% EA/PE) to affordt-butyl N-(3,5-dichloro-4-hydroxy-phenyl)carbamate (35 g, 125.84 mmol,75% yield) was obtained as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ7.19 (s, 1H), 6.27 (br s, 1H), 5.55 (s, 1H), 1.44 (s, 10H).

The mixture of t-butyl N-(3,5-dichloro-4-hydroxy-phenyl)carbamate (33.14g, 119.15 mmol) and 2-bromo-4-fluoro-1-nitro-benzene (31.46 g, 142.98mmol) and Cs₂CO₃ (54.35 g, 166.81 mmol) in CH₃CN (500 mL) was heated to65° C. for 18 h. The mixture was concentrated to remove CH₃CN anddiluted with EA (500 mL) and the organic layer was washed with H₂O (200mL×2). The organic layer was dried over MgSO₄ and concentrated to affordcrude, purified by silica gel chromatography (eluent of 0˜15% EA/PE) toafford t-butyl N-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]carbamate (20 g, 41.83 mmol, 35% yield) obtained as white solid. H NMR(400 MHz, CDCl₃) δ 7.97 (d, J=9.0 Hz, 1H), 7.55 (s, 2H), 7.18 (d, J=2.6Hz, 1H), 6.88 (dd, J=2.6, 9.0 Hz, 1H), 6.60 (s, 1H), 1.56 (s, 9H).

The mixture of t-butylN-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]carbamate (21.5 g,44.97 mmol) and TFA (51.27 g, 449.68 mmol, 33.29 mL) in DCM (200 mL) wasstirred at 20° C. for 4 h. The mixture was concentrated. NaHCO₃ (sat.,aq., 500 mL) was added to mixture. The mixture was stirred at 20° C. for4 h. The precipitated solid was filtered and dried.4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-aniline (16.1 g, 39.18 mmol,87% yield, 92% purity) was obtained as yellow solid.

To a solution of 4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-aniline (5 g,13.23 mmol) in AcOH (60 mL) was added HCl (12 M, 11.02 mL). The mixturewas cooled to 5° C. in an ice bath. A solution of NaNO₂ (2.74 g, 39.68mmol) in H₂O (30 mL) was added to above suspended solution, whilemaintaining the temperature between 5-10° C. The mixture was stirred at5° C. for 30 min. A solution of ethyl N-(2-cyanoacetyl)carbamate (2.48g, 15.87 mmol) in pyridine (25 mL) was added to above light yellow clearsolution slowly. The mixture was stirred at 5° C. for 1 hr and then 20°C. for 1 h. The mixture was filtered and the filtered solid was dilutedwith ethyl acetate (500 mL) and washed with H₂O (200 mL×2). The organiclayer was dried over MgSO₄ and concentrated to afford crude product. Thecrude product was used for the next step without further purification.ethylN-[2-[[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]hydrazono]-2-cyano-acetyl]carbamate(6.7 g, 12.29 mmol, 93% yield) was obtained as red solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.94 (s, 1H), 8.13-8.06 (m, 3H), 7.51 (d, J=2.6 Hz,1H), 7.09 (dd, J=2.7, 9.1 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 1.28 (t,J=7.1 Hz, 3H).

The mixture of ethylN-[2-[[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]hydrazono]-2-cyano-acetyl]carbamate(2 g, 3.67 mmol) and Et3N (1.86 g, 18.34 mmol, 2.55 mL) in DMF (30 mL)was heated to 100° C. and stirred for 18 h under N₂. The mixture wasdiluted with EA (200 mL) and washed with H₂O (100 mL×3) and brine (100mL×3). The organic layer was dried over MgSO₄, the solids were removedby filtration and the filtrate was concentrated under reduced pressure.The crude was purified by silica gel chromatography (eluent of 0˜100%EA/PE then 0˜10% MeOH/EA).2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(1.3 g, 2.60 mmol, 61.74% yield) was obtained as yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.10 (d, J=9.0 Hz, 1H), 7.89 (s, 2H), 7.61 (d,J=2.8 Hz, 1H), 7.10 (dd, J=2.8, 9.1 Hz, 1H).

To a solution of2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(12.1 g, 24.25 mmol) in AcOH (20 mL) was added HCl (70 mL) and themixture was stirred at 120° C. for 16 h. The mixture was concentrated toremove HCl and AcOH. H₂O (80 mL) was added and the mixture was cooled to0° C. The precipitated solid was isolated by filtration and dried toafford2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylicacid (10.06 g, 19.42 mmol, 80% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 13.19-12.22 (m, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.91 (s, 2H),7.63 (d, J=2.6 Hz, 1H), 7.10 (dd, J=2.7, 9.1 Hz, 1H).

The mixture of2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazine-6-carboxylicacid (9.06 g, 17.49 mmol) and DPPA (7.22 g, 26.23 mmol) and Et₃N (7.08g, 69.95 mmol) in t-BuOH (15 mL) was heated to 85° C. for 16 h undernitrogen atmosphere. The mixture was diluted with EA (30 mL) and washedwith H₂O (10 mL×2). The organic layer was dried over MgSO₄ andconcentrated to afford crude. The residue was purified by silica gelchromatography (eluent of 0-50% EA/PE). t-ButylN-[2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate (5.2 g, 8.83 mmol, 45.47% yield) was obtained as yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (br s, 1H), 9.18 (s, 1H), 8.10 (d,J=9.1 Hz, 1H), 7.98 (s, 2H), 7.61-7.55 (m, 1H), 7.08 (dd, J=2.7, 9.1 Hz,1H), 1.46 (s, 9H).

To a solution of t-butylN-[2-[4-(3-bromo-4-nitro-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-tria-zin-6-yl]carbamate(1 g, 1.70 mmol) in THF (20 mL), MeOH (10 mL) and H₂O (5 mL) was addedFe (473.92 mg, 8.49 mmol) and NH₄Cl (453.95 mg, 8.49 mmol). The mixturewas stirred at 80° C. for 2 h. The reaction mixture was diluted with EA(50 mL), filtered and the filtrate was concentrated under reducedpressure to give t-butylN-[2-[4-(4-amino-3-bromo-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(700 mg, 1.25 mmol, 74% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.30 (br s, 1H), 9.15 (s, 1H), 7.88 (s, 2H), 6.87 (d, J=2.8Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.71-6.64 (m, 1H), 5.10 (br s, 2H),1.45 (s, 9H).

To a solution of t-butylN-[2-[4-(4-amino-3-bromo-phenoxy)-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-tr-iazin-6-yl]carbamate(700 mg, 1.25 mmol) in THF (20 mL) was added DIEA (485.35 mg, 3.76mmol), and 4-methylpent-2-enoyl chloride (199.17 mg, 1.50 mmol, 11.69uL) at 25° C. The mixture was stirred at 25° C. for 3 hr. The reactionmixture was diluted with H₂O (50 mL) and extracted with EA (50 mL×3).The combined organic layers were washed with brine (60 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography(eluent 0˜35% THF/PE) to give t-butylN-[2-[4-[3-bromo-4-[[4-methylpent-2-enoyl]amino]phenoxy]-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(370 mg, 564.61 umol, 45.10% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.65 (br s, 1H), 9.52 (s, 1H), 9.09 (br s, 1H), 7.97-7.94(m, 2H), 7.53 (d, J=8.9 Hz, 1H), 7.23 (d, J=2.9 Hz, 1H), 6.87 (s, 1H),6.80 (dd, J=6.3, 15.4 Hz, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 6.18 (br d,J=15.1 Hz, 1H), 1.46 (s, 9H), 1.05 (d, J=6.8 Hz, 6H).

To a solution of t-butylN-[2-[4-[3-bromo-4-[[4-methylpent-2-enoyl]amino]phenoxy]-3,5-dichloro-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(320 mg, 488.31 umol) in dioxane (2 mL) was added TEA (148.24 mg, 1.46mmol, 203.90 uL), and palladium tri-t-butylphosphane (24.96 mg, 48.83umol) at 25° C. Then the mixture was stirred at 130° C. for 1.5 h. LCMSshowed the starting material was consumed completely and desired masswas detected. The reaction mixture was diluted with H₂O (10 mL) andextracted with EA (10 mL×3). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC [Column: Welch Xtimate C18 150×30 mm×5 um; Mobile phase: from50% CH₃CN in water (0.225% FA) to 80% CH₃CN in water (0.225% FA)] togivet-butyl-[2-[3,5-dichloro-4-[(4-isopropyl-2-oxo-1H-quinolin-6-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(20 mg, 34.82 umol, ¹H NMR (400 MHz, DMSO-d₆) δ (br s, 1H), 11.66 (s,1H), 9.15 (br s, 1H), 7.94 (s, 2H), 7.35 (d, J=9.0 Hz, 1H), 7.23 (d,J=2.9 Hz, 1H), 7.11 (dd, J=2.6, 9.0 Hz, 1H), 6.39 (s, 1H), 3.20 (br d,J=6.4 Hz, 1H), 1.46 (s, 9H), 1.21 (d, J=6.8 Hz, 6H)) as a yellow solidand t-butylN-[2-[3,5-dichloro-4-[(3Z)-3-(2-methylpropylidene)-2-oxo-indolin-5-yl]oxy-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(26 mg, 45.26 umol, ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.45 (s,1H), 9.17 (s, 1H), 7.90 (s, 2H), 7.25 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.5Hz, 1H), 6.68 (d, J=10.0 Hz, 1H), 6.55 (dd, J=2.5, 8.5 Hz, 1H), 3.14(qd, J=6.7, 16.5 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J=6.5 Hz, 6H) as ayellow solid.

To a solution of t-butylN-[2-[3,5-dichloro-4-[(4-isopropyl-2-oxo-1H-quinolin-6-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(20 mg, 34.40 umol) in MeOH (1 mL) was added HCl/dioxane (4 M, 43.00 uL)at 15° C. The mixture was stirred at 15° C. for 6 hr. The reactionmixture was concentrated in vacuo. The residue was purified by prep-HPLC[Column: Welch Xtimate C18 150×30 mm×5 um; mobile phase: from 30% CH₃CNin water (0.04% NH₃H₂O+10 mM NH₄HCO₃) to 60% CH₃CN in water (0.04%NH₃H₂O+10 mM NH₄HCO₃)] to give6-amino-2-[3,5-dichloro-4-[(4-isopropyl-2-oxo-1H-quinolin-6-yl)oxy]phenyl]-1,2,4-triazine-3,5-dione(1.95 mg, 4.07 umol, 11.82% yield, 99% purity) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.30 (br s, 1H), 11.65 (s, 1H), 7.95 (s, 2H), 7.34(d, J=8.9 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.11 (dd, J=2.7, 8.9 Hz, 1H),6.56 (br s, 2H), 6.39 (s, 1H), 3.23-3.14 (m, 1H), 1.20 (d, J=6.8 Hz,6H).

To a solution of t-butylN-[2-[3,5-dichloro-4-[(3Z)-3-(2-methylpropylidene)-2-oxo-indolin-5-yl]oxy-phenyl]-3,5-dioxo-1,2,4-triazin-6-yl]carbamate(26 mg, 45.26 umol) in MeOH (1 mL) was added HCl/dioxane (4 M, 0.057 mL)at 15° C. The mixture was stirred at 15° C. for 16 hr. The reactionmixture was concentrated in vacuo to give crude product, that waspurified by prep-HPLC [Column: Welch Xtimate C18 150×30 mm×5 um; mobilephase: from 10% CH₃CN in water (0.2% FA) to 50% CH₃CN in water (0.2% FA)to give6-amino-2-[3,5-dichloro-4-[(3Z)-3-(2-methylpropylidene)-2-oxo-indolin-5-yl]oxy-phenyl]-1,2,4-triazine-3,5-dione(4.64 mg, 9.73 umol, 99.44% purity) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.30 (br s, 1H), 10.44 (s, 1H), 7.91 (s, 2H), 7.24 (d, J=2.5Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.68 (d, J=9.9 Hz, 1H), 6.54 (d, J=2.6Hz, 1H), 6.53-6.50 (m, 2H), 3.14 (td, J=6.5, 9.8 Hz, 1H), 1.14 (d, J=6.5Hz, 6H).

Example 81: Synthesis of Compound 148

Anhydrous THF (20 mL) was added to a mixture of5′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (400 mg, 1.68 mmol) andNaH 60% (1.5 eq., 101 mg) at 0° C., under N₂. The resulting reactionmixture was stirred at 25° C. for 1 h. Then, the mixture was cooled to−78° C. and t-BuLi (2.2 eq., 2.17 mL) was added dropwise and thereaction mixture was stirred at −78° C. for 30 min. Then, a solution of2,2,2-trifluoro-N-(4-formyl-3,5-dimethylphenyl)acetamide (1 eq., 412 mg)in anhydrous THF (5 mL) was added dropwise to the reaction mixture at−78° C. The reaction mixture was then allowed to warm to rt for 2 h andfinally quenched with NH₄Cl (sat., aq., 4 mL) and poured in CH₂Cl₂ (100mL). The organic phase was washed with water (3×), dried over MgSO₄,filtered and evaporated to dryness. The crude mixture was purified byflash chromatography on silica gel (0 to 50% EA in cyclohexane) to give2,2,2-trifluoro-N-(4-(hydroxy(2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)-3,5-dimethylphenyl)acetamide(269 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.38-1.52(m, 4H), 2.20 (s, 6H), 5.75 (d, J=4.0 Hz, 1H), 6.06 (d, J=4.0 Hz, 1H),6.78 (s, 2H), 6.92 (s, 1H), 7.28 (s, 2H), 10.46 (s, 1H), 11.06 (br s,1H) ppm.

Et₃SiH (0.64 mL) and TMSOTf (0.027 mL) were added dropwise to a solutionof2,2,2-trifluoro-N-(4-(hydroxy(2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)-3,5-dimethylphenyl)acetamide(268 mg, 0.66 mmol) in anhydrous CH₂Cl₂ (30 mL) at 0° C. under N₂. Thereaction was stirred at 0° C. for 1 h, at which point the ice bath wasremoved and the reaction was stirred at 25° C. for 16 h. The reactionmixture was quenched with sat. aq. NaHCO₃(20 mL) and extracted withCH₂Cl₂ (3×40 mL). The combined organic layers were washed with brine(100 mL), dried over MgSO₄, filtered and evaporated to dryness to affordN-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-2,2,2-trifluoroacetamide(229 mg, 89%) as a white solid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 1.41-1.48 (m, 4H), 2.18 (s,6H), 3.91 (s, 2H), 6.58 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.75 (d, J=8.0Hz, 1H), 7.35 (s, 2H), 10.43 (s, 1H), 11.06 (br s, 1H) ppm.

NaOH (6 eq., 141 mg) was added to a solution ofN-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-2,2,2-trifluoroacetamide(229 mg, 0.59 mmol) in CH₃OH (25 mL) and water (2.5 mL) under N₂. Themixture was stirred at 60° C. for 23 h. Then, the mixture was quenchedwith water (100 mL). The resulting solution was extracted with CH₂Cl₂(3×100 mL). The combined organic layers were washed with brine (300 mL),dried over MgSO₄, filtered and evaporated to dryness to give5′-(4-amino-2,6-dimethylbenzyl)spiro[cyclopropane-1,3′-indolin]-2′-one(147 mg, 85%) as a white solid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 1.40-1.46 (m, 4H), 2.02 (s,6H), 3.76 (s, 2H), 4.71 (s, 2H), 6.26 (s, 2H), 6.61 (d, J=8.0 Hz, 1H),6.68 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 10.39 (s, 1H) ppm.

t-Butyl nitrite (0.090 mL) and pyridine (0.12 mL) were added to asolution of5′-(4-amino-2,6-dimethylbenzyl)spiro[cyclopropane-1,3′-indolin]-2′-one(1 eq., 147 mg, 0.503 mmol) and ethyl N-(2-cyanoacetyl)carbamate (118mg) in anhydrous CH₃CN (15.5 mL) under N₂. The reaction mixture wasstirred at 60° C. for 1.5 h. After cooling to rt, NaOAc (6 eq., 248 mg)was added and the reaction mixture was heated at 80° C. for 3 h.Additional NaOAc (82 mg) was added and heating was pursued for 64 h. Thereaction mixture was cooled to 0° C. and water (50 mL) was added. Themixture was stirred for 30 min at 0° C. and the resulting solution wasextracted with EA (3×20 mL). The combined organic layers were dried overMgSO₄, filtered and evaporated to dryness. The crude mixture waspurified by flash chromatography on silica gel (0 to 7.5% CH₃OH inCH₂Cl₂) to give2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(143 mg, 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.42-1.50(m, 4H), 2.24 (s, 6H), 3.98 (s, 2H), 6.59 (d, J=8.0 Hz, 1H), 6.76 (d,J=8.0 Hz, 1H), 6.78 (s, 1H), 7.16 (s, 2H), 10.45 (s, 1H), 12.98 (br s,1H).

Example 82: Synthesis of Compound 149

Anhydrous THF (6 mL) was added to a mixture of6-bromo-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (preparedaccording to Bioorganic & Medicinal Chemistry Letters 2005, 15(15),pages 3600-3603, 300 mg, 1.18 mmol) and NaH 60% (70.6 mg, 1.76 mmol) at0° C., under N₂. The resulting reaction mixture was stirred at rt for 1h. Then, the mixture was cooled to −78° C. and t-BuLi (1.5 mL, 2.59mmol, 1.7 M in pentane) was added dropwise and the reaction mixture wasstirred at −78° C. for 1 h. Then, a solution of4-bromo-2,6-dimethylbenzaldehyde (250.6 mg, 1.18 mmol) in anhydrous THF(3.8 mL) was added dropwise to the reaction mixture at −78° C. Thereaction mixture warmed to rt for 1 h and then quenched with sat. aq.NH₄Cl and extracted with CH₂Cl₂ (3×). The combined organic phases werewashed with water (3×), dried over Na₂SO₄, filtered and evaporated todryness. The crude mixture was purified by flash chromatography onsilica gel (0 to 60% AcOEt in cyclohexane) to give6-((4-bromo-2,6-dimethylphenyl)(hydroxy)methyl)-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(277 mg, 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.36-1.43(m, 6H), 2.22 (s, 6H), 4.53 (p, J=6.9 Hz, 1H), 5.85 (d, J=3.3 Hz, 1H),6.12 (d, J=3.0 Hz, 1H), 6.56 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H),7.19 (s, 1H), 7.21 (s, 2H), 10.66 (s, 1H) ppm.

Et₃SiH (0.69 mL, 4.27 mmol) and TMSOTf (28.8 μL, 0.16 mmol) were addeddropwise to a solution of6-((4-bromo-2,6-dimethylphenyl)(hydroxy)methyl)-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(277 mg, 0.71 mmol) in anhydrous CH₂Cl₂ (32.2 mL) at 0° C. under N₂. Thereaction was stirred at 0° C. for 30 min, at which point the ice bathwas removed and the reaction was stirred at rt for 2 h. The reactionmixture was quenched with sat. aq. NaHCO₃ and extracted with CH₂Cl₂(3×). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and evaporated to dryness providing6-(4-bromo-2,6-dimethylbenzyl)-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(242 mg, 91%) as a white solid which was used in the next step withoutfurther purification.

A solution of6-(4-bromo-2,6-dimethylbenzyl)-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(195 mg, 0.52 mmol),6-amino-4-[(benzyloxy)methyl]-2,3,4,5-tetrahydro-1,2,4-triazine-3,5-dione(142.6 mg, 0.57 mmol), K₂CO₃ (288.8 mg, 2.09 mmol), CuBr (74.9 mg, 0.52mmol) and trans-N,N-dimethylcyclohexane-1,2-diamine (74.3 mg, 0.52 mmol)in anhydrous DMSO (3.9 mL) under N₂ was stirred at 120° C. for 4 h.After cooling to rt, the reaction mixture was diluted in water and wasfiltered. The precipitate was washed with water and was dissolved inCH₂Cl₂. The solution was dried with Na₂SO₄, filtered and evaporated todryness. The crude mixture was purified by flash chromatography onsilica gel (0% to 5% CH₃OH in CH₂Cl₂) to give6-amino-4-((benzyloxy)methyl)-2-(4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione(81 mg, 29%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (d,J=6.9 Hz, 6H), 2.25 (s, 6H), 4.06 (s, 2H), 4.51 (p, J=6.9 Hz, 1H), 4.66(s, 2H), 5.41 (s, 2H), 6.38 (s, 2H), 6.46 (d, J=7.8 Hz, 1H), 6.83 (d,J=7.9 Hz, 1H), 7.00 (s, 1H), 7.19 (s, 2H), 7.26-7.35 (m, 5H), 10.63 (s,1H) ppm.

BBr₃ (1.2 mL, 1.2 mmol, 1 M in CH₂Cl₂) was added dropwise to a solutionof give6-amino-4-((benzyloxy)methyl)-2-(4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione(81 mg, 0.15 mmol) in CH₂Cl₂ (50 mL) at 0° C. under N₂. The reactionmixture was stirred at 0° C. for 2 h. Afterwards, cold CH₃OH was addeddropwise at 0° C. and the reaction mixture slowly warmed to rt, then wasevaporated to dryness and the crude mixture was purified bychromatography on silica gel (0% to 10% CH₃OH in CH₂Cl₂). The resultingproduct was purified by reverse phase flash chromatography (5 to 100%CH₃CN in water (0.1% TFA)) to give6-amino-2-(4-((3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-3,5-dimethylphenyl)-1,2,4-triazine-3,5(2H,4H)-dione(26 mg, 41%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (d,J=6.9 Hz, 6H), 2.23 (s, 6H), 4.04 (s, 2H), 4.51 (hept, J=7.0 Hz, 1H),6.30 (s, 2H), 6.44 (d, J=8.0 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 7.01 (s,1H), 7.20 (s, 2H), 10.67 (s, 1H), 12.07 (s, 1H) ppm.

Example 83: Synthesis of Compound 150

6-Amino-2-(3,5-dimethyl-4-((2′-oxospiro[cyclopentane-1,3′-indolin]-5′-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewas prepared using a method analogous to that described for compound 149where 5′-bromospiro[cyclopentane-1,3′-indolin]-2′-one was employed inthe first step instead of6-bromo-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one. ¹H NMR (400MHz, DMSO-d₆) δ 1.65-1.73 (m, 2H), 1.84-1.98 (m, 6H), 2.21 (s, 6H), 3.96(s, 2H), 6.29 (s, 2H), 6.59 (dd J=7.9 Hz, 1H); 6.69 (d, J=8.0 Hz, 1H),7.03 (s, 1H), 7.19 (s, 2H), 10.17 (s, 1H), 12.07 (s, 1H).

Example 84: Synthesis of Compound 151

6-Amino-2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewas prepared using a method analogous to that described for compound 149where 5′-bromospiro[cyclopropane-1,3′-indolin]-2′-one was employed inthe first step instead of6-bromo-1-isopropyl-1,3-dihydro-2H-benzo[d]imidazol-2-one. ¹H NMR (400MHz, DMSO-d₆) δ 1.42-1.49 (m, 4H), 2.20 (s, 6H), 3.94 (s, 2H), 6.30 (s,2H), 6.58 (dd, J=8.0 Hz, 1.9 Hz, 1H), 6.76 (dd, J=5.2 Hz, 3.3 Hz, 2H),7.19 (s, 2H), 10.44 (s, 1H), 12.08 (br s, 1H) ppm.

Example 85: Synthesis of Compound 152

KOH (10 eq., 140 mg, 2.49 mmol) was added to a solution of2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile(103 mg, 0.25 mmol) in water (1.3 mL) and EtOH (1.3 mL) under N₂. Thereaction mixture was stirred at 80° C. for 2 h. The reaction mixture wasevaporated to dryness, water was added and aqueous 1N HCl solution wasadded until acidic pH. Then, the aqueous layer was extracted with EtOAc(3×). The combined organic layers were dried with Na₂SO₄, filtered andevaporated to dryness providing2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (102 mg, 95%) as a brown oil which was used without furtherpurification.

A solution of2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylicacid (1 eq., 69 mg, 0.16 mmol) in mercaptoacetic acid (25 eq., 276 μL, 4mmol) was stirred rapidly and heated to 100° C. for 3 h. After coolingto rt, the reaction mixture was diluted in water, filtered and washedwith water. The precipitate was dissolved in MeOH and evaporated todryness. The crude mixture was purified by flash chromatography onsilica gel (0% to 5% MeOH in DCM), triturated with MeCN (2×) andco-evaporated with EtOH (2×) to give2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione(11 mg, 18%) as a yellow solid. ¹H-NMR (DMSO-d₆, 400 MHz) δ 1.43-1.48(m, 4H), 2.23 (s, 6H), 3.96 (s, 2H), 6.59 (d, J=7.7 Hz, 1H), 6.77 (d,J=8.0 Hz, 2H), 7.17 (s, 2H), 7.61 (s, 1H), 10.44 (s, 1H), 12.30 (br s,1H) ppm.

Example 86: Synthesis of Compound 153

2-(3,5-Dimethyl-4-((2′-oxospiro[cyclobutane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrilewas prepared using a method analogous to that described for thepreparation of2-(3,5-dimethyl-4-((2′-oxospiro[cyclopropane-1,3′-indolin]-5′-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile,where 5′-bromospiro[cyclobutane-1,3′-indolin]-2′-one was used instead of5′-bromospiro[cyclopropane-1,3′-indolin]-2′-one. ¹H-NMR (DMSO-d₆, 400MHz) δ 2.11-2.27 (m, 10H), 2.37-2.43 (m, 2H), 4.04 (s, 2H), 6.60 (dd,J=8.0 Hz, 2.0 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 7.18 (s, 2H), 7.37 (s,1H), 10.13 (s, 1H), 12.99 (br s, 1H) ppm.

Example 87: Preparation of Compound 154

To a solution of 6-bromo-3-methyl-1H-quinolin-2-one (3 g, 12.60 mmol) inTHE (50 mL) was added NaH (2.02 g, 50.40 mmol, 60% purity) at 20° C. Themixture was stirred at 40° C. for 0.5 hr. Then SEM-Cl (4.20 g, 25.20mmol, 4.46 mL) was added. The mixture was stirred at 40° C. for 16 h.The reaction mixture was quenched by addition of NH₄C₁ (sat., aq., 20mL) at 10° C., and then diluted with H₂O (60 mL) and extracted with EA(60 mL×3). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by flash silica gel chromatography(EA/PE=0˜10%) to give6-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (3.25 g,8.82 mmol, 70% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.64(d, J=2.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.52-7.44 (m, 2H), 5.79 (s, 2H),3.77-3.65 (m, 2H), 2.29 (d, J=0.9 Hz, 3H), 1.03-0.89 (m, 2H), 0.04-0.05(m, 9H).

A mixture of6-bromo-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (3.25 g,8.82 mmol, 1 eq), Pin₂B₂ (3.36 g, 13.24 mmol, 1.5 eq), KOAc (2.60 g,26.47 mmol), PdCl₂(dppf) (720.55 mg, 882.34 umol) in dioxane (60 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 100° C. for 16 hr under N₂ atmosphere. The reaction mixturewas diluted with H₂O (100 mL) and extracted with EA (100 mL×3). Thecombined organic layers were washed with brine (100 mL×2), dried overNa₂SO₄, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography (EA/PE=0˜10%) to give3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)quinolin-2-one(4.1 g, crude) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H),7.93 (dd, J=1.1, 8.4 Hz, 1H), 7.64-7.54 (m, 2H), 5.83 (s, 2H), 3.79-3.66(m, 2H), 2.29 (s, 3H), 1.41 (s, 12H), 1.02-0.89 (m, 2H), 0.00 (s, 9H).

To a solution of3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2-trimethylsilylethoxymethyl)quinolin-2-one(4.1 g, 9.87 mmol) in acetone (60 mL) and H₂O (30 mL) was added NaIO₄(21.11 g, 98.70 mmol, 5.47 mL) and NH₄OAc (7.61 g, 98.70 mmol) at 20° C.The mixture was stirred at 20° C. for 16 hr. The reaction mixture wasdiluted with H₂O (60 mL) and extracted with EA (60 mL×3). The combinedorganic layers were washed with brine (100 mL), dried over anhydrousNa₂SO₄, the solids were removed under reduced pressure and the filtratewas concentrated under reduced pressure to give[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]boronic acid(2.7 g, 7.38 mmol, 75% yield, 91% purity) as a pink solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.20 (s, 2H), 8.09 (s, 1H), 8.03-7.95 (m, 1H), 7.90-7.81(m, 1H), 7.55 (d, J=8.5 Hz, 1H), 5.79 (s, 2H), 3.68 (t, J=7.9 Hz, 2H),2.26-2.16 (m, 3H), 0.94 (t, J=7.9 Hz, 2H), 0.05-0.05 (m, 9H).

To a solution of[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]boronic acid(500 mg, 1.50 mmol) in DMF (20 mL) was added 4 Å MS (5 g, 1.50 mmol),N-(3,5-dichloro-4-hydroxy-phenyl)-N,N-dimethyl-formamidine (384.69 mg,1.65 mmol), bis(trifluoromethylsulfonyloxy)copper (542.64 mg, 1.50 mmol)and triethylamine (759.08 mg, 7.50 mmol) at 15° C. The mixture wasstirred at 15° C. for 16 hr under 02. The reaction mixture was dilutedwith H₂O (50 mL) and extracted with EA (50 mL×2). The combined organiclayers were washed with brine (50 mL×2), dried over Na₂SO₄, the solidswere removed by filtration and the filtrate was concentrated underreduced pressure to give a residue. The residue was purified by flashsilica gel chromatography (0˜35% EA/PE=0˜35%) to giveN-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]-N,N-dimethylformamidine(250 mg, 480.29 umol, 32% yield) as a green solid. ¹H NMR (400 MHz,CDCl₃) δ 7.56 (s, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.43 (s, 1H), 7.11 (dd,J=2.8, 9.2 Hz, 1H), 7.01 (s, 2H), 6.81 (d, J=2.9 Hz, 1H), 5.77 (s, 2H),3.73-3.66 (m, 2H), 3.07 (br d, J=11.0 Hz, 6H), 2.23 (d, J=0.9 Hz, 3H),0.98-0.92 (m, 2H), −0.01-0.04 (m, 8H), −0.01-0.04 (m, 1H).

To a solution ofN-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]-N,N-dimethyl-formamidine (658 mg, 1.26 mmol) in isopropanol (20mL) was added NH₂NH₂.H₂O (630.76 mg, 12.60 mmol) at 20° C. The mixturewas stirred at 80° C. for 12 hr under N₂. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with EA (30 mL×2). The aqueousphase was adjusted to pH=7 with 1M aq. HCl. The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography (EA/PE=0˜30%) to give6-(4-amino-2,6-dichloro-phenoxy)-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (387 mg, 831.46 umol, 66% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.77 (s, 1H), 7.48 (d, J=9.3 Hz, 1H), 7.10 (dd,J=2.9, 9.3 Hz, 1H), 6.94 (d, J=2.9 Hz, 1H), 6.73 (s, 2H), 5.67 (s, 4H),3.60-3.54 (m, 2H), 2.08 (d, J=0.6 Hz, 3H), 0.89-0.81 (m, 2H),−0.04-−0.15 (m, 9H).

To a mixture of6-(4-amino-2,6-dichloro-phenoxy)-3-methyl-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (387 mg, 665.17 umol, 80% purity) in AcOH (5 mL) wasadded HCl (12 M, 0.554 mL). Then dropwise a solution of NaNO₂ (137.69mg, 2.00 mmol) in H₂O (5 mL) while maintaining the temperature below 0°C. After the addition was complete, the reaction mixture was stirred for0.5 h. A mixture of ethyl N-(2-cyanoacetyl)carbamate (207.72 mg, 1.33mmol) in pyridine (2.5 mL) was added drop-wise to the resultingdiazonium salt solution below 0° C. and stirred for an additional 2 h.The reaction mixture was diluted with H₂O (50 mL), then extracted withEA (50 mL×3). The combined organic layers were washed with brine (60mL), dried over anhydrous Na₂SO₄, the solids were removed by filtrationand the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography (EA in PE=0˜40%) to give ethylN-[2-cyano-2-[[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]hydrazono]acetyl]carbamate(315 mg, 497.97 umol, 74.8% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.93 (br s, 1H), 10.89 (s, 1H), 8.07 (s, 2H), 7.77 (s, 1H),7.51 (d, J=9.3 Hz, 1H), 7.17 (dd, J=3.0, 9.3 Hz, 1H), 7.02 (d, J=3.0 Hz,1H), 5.69 (s, 2H), 4.24-4.18 (m, 2H), 3.58 (t, J=7.9 Hz, 2H), 2.08 (d,J=0.8 Hz, 3H), 1.25-1.19 (m, 3H), 0.86 (t, J=7.9 Hz, 2H), −0.05-−0.12(m, 9H).

N-[2-cyano-2-[[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]hydrazono]acetyl]carbamate(315 mg, 497.97 umol) in AcOH (10 mL) was added NaOAc (204.25 mg, 2.49mmol). The reaction mixture was concentrated in vacuo, then quenched byaddition of sat. aq. NaHCO₃(15 mL), then diluted with H₂O (25 mL) andextracted with EA (25 mL×3). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give2-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(300 mg, 406.48 umol, 81.6% yield, 79% purity) as an orange solid.

A mixture of2-[3,5-dichloro-4-[[3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)-6-quinolyl]oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(265 mg, 359.06 umol, 79.5% purity), TBAF (1 M, 10.77 mL) in THF (10 mL)was degassed and purged with N₂ three times, then the mixture wasstirred at 90° C. for 16 h under N₂. The reaction mixture was quenchedby NH₄C₁ (sat., aq., 20 mL) at 15° C., and then diluted with H₂O (10 mL)and extracted with EA (20 mL×3). The combined organic layers were washedwith sat. NH₄Cl (30 mL), dried over Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified by prep-HPLC [Column: Welch Xtimate C18 150×30 mm×5um; mobile phase: from 48% CH₃CN in water (0.225% FA) to 78% CH₃CN inwater (0.225% FA)] to give2-[3,5-dichloro-4-[(3-methyl-2-oxo-1H-quinolin-6-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile(60.05 mg, 128.59 umol, 35.8% yield, 98% purity) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (br s, 1H), 11.75 (s, 1H), 7.82(s, 2H), 7.76 (s, 1H), 7.31 (d, J=9.0 Hz, 1H), 7.17 (dd, J=2.8, 8.9 Hz,1H), 7.00 (d, J=2.8 Hz, 1H), 2.05 (s, 3H).

Example 88: Synthesis of Compound 156

A 40 mL vial was charged with 2,2,6,6-tetramethylpiperidine (10.3 g,73.2 mmol) in THF (100 mL) under nitrogen. n-butyllithium (26.8 mL, 67.1mmol) was added dropwise at −75° C. The reaction was warmed to 0° C. andstirred for 30 min. 3,6-dichloropyridazine (5 g, 33.6 mmol) in THF (100mL) was added dropwise at −75° C. The reaction was stirred for 30 min.2,3-dihydro-1H-inden-1-one (5.32 g, 40.3 mmol) in THF (50 mL) was addeddropwise at −75° C. The reaction was stirred for 90 min at −75° C. Thereaction was stirred for 90 min at −75° C. The resulting solution wasquenched with NH₄C₁ (sat., aq., 100 mL). The resulting solution wasextracted with EA (3×100 mL) and the organic layers were combined,washed with brine (2×100 mL), dried over anhydrous sodium sulfate, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn with EA/PE (1/4) to provide 2.28 g (yield 12%) of1-(3,6-dichloropyridazin-4-yl)-2,3-dihydroinden-1-ol as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (s, 1H), 7.28-7.37 (m, 2H), 7.14-7.19(m, 1H), 6.41 (m, 1H), 3.21-3.32 (m, 1H), 3.02-3.11 (m, 1H), 2.70-2.81(m, 1H), 2.19-2.27 (m, 1H). LCMS (ESI, m/z): 281 [M+H]⁺.

A 40 mL vial was charged with1-(3,6-dichloropyridazin-4-yl)-2,3-dihydroinden-1-ol (800 mg, 2.85mmol), 4-methylbenzenesulfonic acid (245 mg, 1.42 mmol), toluene (10mL). The reaction was stirred overnight at 60° C. The resulting solutionwas quenched with water (20 mL). The resulting solution was extractedwith EA (3×20 mL) and the organic layers were combined, washed withbrine (2×20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column with EA/PE (1/9) to provide 520 mg (yield 50%) of3,6-dichloro-4-(3H-inden-1-yl)pyridazine as a yellow solid. ¹H NMR (300MHz, CDCl₃) δ 7.59-7.62 (m, 2H), 733-7.40 (m, 2H), 723-7.26 (m, 1H),6.92 (t, J=2.1 Hz, 1H), 3.68 (br, 2H). LCMS (ESI, m z):263 [M+H]⁺.

A 100 mL round-bottom flask was charged with3,6-dichloro-4-(3H-inden-1-yl)pyridazine (800 mg, 0.380 mmol),platinumoxidehydrate (400 mg), EA (5 mL), ethanol (5 mL). The content ofthe flask was placed under an atmosphere of hydrogen. The reaction wasstirred overnight at rt. The solids were filtered out. The filtrate wasconcentrated under reduced pressure. The residue was chromatographed ona silica gel column with EA/PE (12/88) to provide 165 mg (yield 19%) of3,6-dichloro-4-(2,3-dihydro-1H-inden-1-yl)pyridazine as a white solid.¹H NMR (300 MHz, CDCl₃) δ 7.31-7.40 (m, 3H), 7.08 (d, J=7.5 Hz, 1H),7.01 (s, 1H), 4.74 (t, J=7.5 Hz, 1H), 3.05 (t, J=7.5 Hz, 2H), 2.74-2.86(m, 1H), 1.94-2.06 (m, 1H). LCMS (ESI, m z): 265 [M+H]⁺.

A 40 mL vial was charged with3,6-dichloro-4-(2,3-dihydro-1H-inden-1-yl)pyridazine (200 mg, 0.754mmol), t-butylN-[2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(382 mg, 0.981 mmol), potassium carbonate (313 mg, 2.26 mmol), CuI (57.5mg, 0.302 mmol), DMSO (10 mL) under nitrogen. The reaction was stirredfor 16 h at 110° C. The reaction was quenched by water (10 mL). Theresulting solution was extracted with ethyl acetate (3×20 mL) and theorganic layers were combined, washed with brine (2×10 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column withethyl acetate/petroleum ether (1/1) to provide 120 mg (yield 21%) of6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(2,3-dihydro-1H-inden-1-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a brown solid. LCMS (ESI, m z): 517 [M+H]⁺.

A 40 mL vial was charged with6-amino-2-(3,5-dichloro-4-[[6-chloro-5-(2,3-dihydro-1H-inden-1-yl)pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(120 mg, 0.232 mmol, 1.00 equiv), sodium acetate (114 mg, 1.39 mmol),acetic acid (5 mL) under nitrogen. The reaction was stirred overnight at100° C. The reaction was poured into water (5 mL). The solids werecollected by filtration to provide the crude product. The crude productwas purified by preparative HPLC using the following gradientconditions: Column: XBridge Prep OBD C18, 19×250 mm, Sum; mobile phaseA:Water (0.05% TFA), mobile phase B: CH₃CN; Flow rate:25 mL/min;Gradient:48 B to 68 B in 7 min; 220 nm; RT1:5.38; Purification resultedin 26.6 mg (yield 31%) of6-amino-2-(3,5-dichloro-4-[[5-(2,3-dihydro-1H-inden-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dioneas a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.27-12.36 (m,2H), 7.84 (s, 2H), 7.33 (d, J=6.3 Hz, 1H), 7.16-7.26 (m, 3H), 7.03 (s,1H), 6.53 (s, 2H), 4.55 (t, J=7.2 Hz, 1H), 2.88-3.09 (m, 2H), 2.42-2.45(m, 1H), 2.08-2.18 (m, 1H). LCMS (ESI, m/z): 499 [M+H]⁺.

Example 89: Synthesis of Compound 157

To a solution of5-bromo-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine (1.9 g,4.83 mmol) in MeOH (20 mL) and THF (5 mL) was added Et₃N (1.47 g, 14.49mmol, 2.02 mL, 3 eq) and Pd(dppf)Cl₂ (706.97 mg, 0.966 mmol), and themixture was stirred at 80° C. for 12 h under CO (50 psi), then dilutedwith H₂O (100 mL) and extracted with EA (100 mL×3). The combined organiclayers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The crude was purified by silica gelchromatography (EA in PE 0˜30%) to give methyl3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c] pyridine-5-carboxylate(1.61 g,4.29 mmol, 88.77% yield, 99.2% purity) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 9.34 (d, J=0.6 Hz, 1H), 8.38 (d, J=0.6 Hz, 1H), 7.80(d, J=8.4 Hz, 2H), 7.49 (d, J=0.8 Hz, 1H), 7.28-7.23 (m, 3H), 4.02 (s,3H), 3.14 (spt, J=6.8 Hz, 1H), 2.37 (s, 3H), 1.35 (d, J=6.9 Hz, 6H).

To a solution of methyl3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carboxyl-ate(1.0 g, 2.66 mmol) in THF (30 mL) was added DIBAL-H (1 M, 7.99 mL)dropwise at −65° C. After the addition, the resulting mixture wasstirred at −65° C. for 0.5 hr under N₂. The reaction mixture wasquenched with methanol (10 mL) and citric acid (sat., aq., 10 mL). Themixture was diluted with H₂O (100 mL) and extracted with EA (50 mL×3).The combined organic layers were washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive a residue, which was purified by silica gel chromatography (eluentof 0-15% EA/PE) to give3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carbaldehyde(807 mg, 2.28 mmol, 85.61% yield, 96.694% purity) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 10.18 (s, 1H), 9.42 (d, J=0.8 Hz, 1H), 8.23 (d,J=0.9 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.53 (d, J=0.8 Hz, 1H), 7.31 (d,J=8.3 Hz, 2H), 3.16 (td, J=6.8, 13.4 Hz, 1H), 2.40 (s, 3H), 1.37 (d,J=6.9 Hz, 6H).

To a solution of 5-bromo-2-iodo-1,3-dimethyl-benzene (544.88 mg, 1.75mmol) in THE (20 mL) was added dropwise n-BuLi (2.5 M, 0.701 mL) at −70°C. over 30 min. After addition, the mixture was stirred at −70° C. for 1h, then3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-carbaldehyde(200 mg, 584.09 umol) in THF (2 mL) was added dropwise at −70° C. Theresulting mixture was stirred at −70° C. for 1 h. Then the mixture wasstirred for 12 hr at 20° C. The reaction mixture was quenched byaddition of NH₄Cl (sat., aq., 80 mL) at 15° C., extracted with EA (40mL×3). The combined organic layers were combined with those of previousbatches, washed with H₂O (60 mL), dried over Na₂SO₄, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure to give a residue. The residue was purified by flash silica gelchromatography (eluent of 0˜15% EA/PE) to give(4-bromo-2,6-dimethyl-phenyl)-[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methanol(341 mg, 646.48 umol) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.15(d, J=1.0 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.33 (d, J=1.0 Hz, 1H), 7.21(s, 2H), 7.09 (s, 2H), 6.87 (s, 1H), 6.13 (s, 1H), 5.25 (s, 1H), 2.85(dd, J=6.0, 6.9 Hz, 1H), 2.31 (s, 3H), 2.10 (s, 6H), 1.13 (dd, J=1.9,6.9 Hz, 6H).

(4-Bromo-2,6-dimethyl-phenyl)-[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methanol(1.11 g, 2.10 mmol), and HI (1.47 g, 6.31 mmol, 0.864 mL, 55% pure) weretaken up into a microwave tube in AcOH (24 mL). The sealed tube washeated at 140° C. for 1 h in the microwave. The reaction mixture wasquenched by addition of NaHCO₃ (sat., aq., 50 mL) at 25° C., thendiluted with H₂O (20 mL) and extracted with EA (40 mL×2). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by silica gel chromatography (eluent of 0˜15%EA/PE) to give5-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine(920 mg, 1.80 mmol, 85% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃)δ 9.12 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.28 (d, J=0.9 Hz, 1H), 7.20 (s,1H), 7.18 (s, 1H), 7.15 (s, 2H), 6.75 (s, 1H), 4.16 (s, 2H), 2.84 (spt,J=6.8 Hz, 1H),2.33-2.26 (m, 3H), 2.15 (s, 6H), 1.13 (d, J=6.9 Hz, 6H).

A mixture of5-[(4-bromo-2,6-dimethyl-phenyl)methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine(340 mg, 398.25 umol), Pin₂B₂ (202.26 mg, 796.50 umol),Pd(dppf)Cl₂.CH₂Cl₂ (32.52 mg, 39.82 umol), KOAc (97.71 mg, 995.62 umol)in DMSO (5 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 130° C. for 16 hr under N₂ atmosphere. Thereaction mixture was diluted with H₂O (20 mL) and extracted with EA (20mL×3). The combined organic layers were washed with brine (30 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product was combined with a previous batch, thenpurified by chromatography on a silica gel eluted with PE: EA (from 1/0to 6/1) to afford5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine(350 mg, crude) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.12 (d,J=0.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.45 (s, 2H), 7.24 (d, J=1.0 Hz,1H), 7.17 (s, 2H), 6.71 (s, 1H), 4.23 (s, 2H), 2.79 (td, J=6.5, 13.4 Hz,1H), 2.29 (s, 3H), 2.17 (s, 6H), 1.29 (s, 12H), 1.10 (d, J=6.8 Hz, 6H).

A mixture of5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine(680 mg, 1.22 mmol), NaIO₄ (781.21 mg, 3.65 mmol, 202.39 uL), NH₄OAc(281.53 mg, 3.65 mmol) in acetone (20 mL) and H₂O (10 mL) was stirred at25° C. for 42 hr. The reaction mixture was diluted with H₂O (30 mL) andextracted with EA (30 mL×3). The combined organic layers were washedwith brine (20 mL×3), dried over Na₂SO₄, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Thecrude was purified by prep-TLC (SiO₂, PE:EA=1:2) to afford4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]boronicacid (380 mg, 785.31 umol, 64.5% yield, 98% purity) as a white solid.

A mixture of 6-amino-4-(benzyloxymethyl)-2H-1,2,4-triazine-3,5-dione(186.22 mg, 750.18 umol),[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]boronicacid (330 mg, 681.98 umol), pyridine (107.89 mg, 1.36 mmol), 4A MS (5 g,681.98 umol) and Cu(OAc)₂ (61.93 mg, 340.99 umol) in DMF (10 mL) wasdegassed and purged with 02 for 3 times, and then the mixture wasstirred at 60° C. for 16 hr under 02 atmosphere. EA (60 mL) was addedand stirred at 25° C. for 10 min. Then filtered and filtrate was washedwith H₂O (20 mL×3), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude was purified by prep-TLC(SiO₂, PE:EA=1:2) to give6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(120 mg, 138.10 umol, 20% yield, 78% purity) as a yellow gum. ¹H NMR(400 MHz, CDCl₃) δ 9.12 (s, 1H), 7.72 (d, J=8.3 Hz, 3H), 7.35-7.23 (m,7H), 7.18-7.13 (m, 4H), 6.83 (s, 1H), 5.52 (s, 2H), 4.69 (s, 2H), 4.22(s, 2H), 2.90-2.81 (m, 2H), 2.30 (s, 4H), 2.22 (s, 6H), 1.13 (d, J=6.9Hz, 6H).

To a solution of6-amino-4-(benzyloxymethyl)-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridine-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(120 mg, 138.10 umol) in DCM (5 mL) was added BBr₃ (276.79 mg, 1.10mmol, 0.106 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. Thereaction mixture was added dropwise to methanol (5 mL) at 0° C. andconcentrated under reduced pressure to give6-amino-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(160 mg, crude) as a yellow solid.

To a solution of6-amino-2-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[2,3-c]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(160 mg, 286.40 umol) in THF (6 mL) was added TBAF (1 M, 5.73 mL) underN₂. The mixture was stirred at 65° C. for 16 hr. The reaction mixturewas quenched by addition of sat. aq. NH₄Cl (10 mL) at 25° C., thendiluted with H₂O (10 mL) and extracted with EA (20 mL×3). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC [Column: Welch Xtimate C18 150×30 mm×5 um;mobile phase: from 15% CH₃CN in water (0.225% FA) to 45% CH₃CN in water(0.225% FA)] to give6-amino-2-[4-[(3-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-1,2,4-triazine-3,5-dione(12.34 mg, 30.30 umol, 10.6% yield, 99% purity) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.15 (br s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.27(d, J=2.0 Hz, 1H), 7.18 (s, 2H), 7.13 (s, 1H), 6.31 (s, 2H), 4.18 (s,2H), 3.01 (td, J=7.0, 13.7 Hz, 1H), 2.31 (s, 6H), 1.23 (d, J=6.9 Hz,6H).

Example 90: Synthesis of Compound 159

To a stirred mixture of 3,4,6-trichloropyridazine (4.00 g, 21.808 mmol)and 3,3-dimethylazetidine (2.93 g, 23.989 mmol) in DMF (50 mL) was addedK₂CO₃ (9.04 g, 65.424 mmol) in portions at rt. The resulting mixture wasstirred for 3 h at 40° C. and quenched with water (150 mL) at rt. Theresulting mixture was filtered, the filter cake was washed with water(2×50 mL) and dried under IR lamp to afford3,6-dichloro-4-(3,3-dimethylazetidin-1-yl)pyridazine (4.6 g, 88.15%) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ 6.21 (s, 1H), 4.00 (s, 4H),1.38 (s, 6H). LCMS (ESI, m z): 232 [M+H]⁺.

To a stirred mixture of3,6-dichloro-4-(3,3-dimethylazetidin-1-yl)pyridazine (4.60 g, 19.818mmol) in methanol (30 mL) was added NaOCH₃ (1.28 g, 23.693 mmol)dropwise at rt. The resulting mixture was stirred overnight at 60° C.and concentrated under reduced pressure. Then water (60 mL) was added.The resulting mixture was filtered, the filter cake was washed withwater (2×40 mL) and dried under IR lamp to afford6-chloro-4-(3,3-dimethylazetidin-1-yl)-3-methoxypyridazine (4.22 g, 87%)as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 6.02 (s, 1H), 4.03 (s, 3H),3.86-3.91 (m, 4H), 1.35 (s, 6H). LCMS (ESI, m z): 228 [M+H]⁺.

To a stirred mixture of6-chloro-4-(3,3-dimethylazetidin-1-yl)-3-methoxypyridazine (4.00 g,17.568 mmol),N-(3,5-dichloro-4-hydroxyphenyl)-N,N-dimethylmethanimidamide (4.09 g,17.568 mmol), Pd₂(dba)₃ (2.73 g, 2.635 mmol) and(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine(1.46 g, 2.631 mmol) in dioxane (80 mL) was added Cs₂CO₃ (11.45 g,35.135 mmol) in portions at rt. The resulting mixture was stirredovernight at 110° C. under nitrogen. The resulting mixture wasconcentrated under reduced pressure and diluted with water (60 mL). Theresulting mixture was extracted with ethyl acetate (3×120 mL) and theorganic layers were combined, washed with brine (2×80 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith CH₂Cl₂/methanol (40/1) to affordN-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-methoxypyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(6 g, 74.05%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (s,1H), 7.07 (s, 2H), 6.11 (s, 1H), 3.81-3.91 (m, 7H), 2.90-3.05 (m, 6H),1.26-1.30 (m, 6H). LCMS (ESI, m z): 424 [M+H]⁺.

To a stirred mixture ofN-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-methoxypyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(2.00 g, 4.713 mmol) in CH₃CN (20 mL) was added TMSI (1.89 g, 9.446mmol) dropwise at rt. The resulting mixture was stirred overnight at 70°C. and quenched by water (50 mL). The resulting solution was extractedwith EA (3×60 mL) and the organic layers were combined, washed withbrine (2×50 mL), dried over anhydrous sodium sulfate, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith CH₂Cl₂/methanol (16:1) to affordN-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(950 mg, 44.70%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.62(s, 1H), 7.85 (s, 1H), 7.02 (s, 2H), 5.80 (s, 1H), 3.59-4.13 (m, 4H),3.01 (s, 3H), 2.89 (s, 3H), 1.24 (s, 6H). LCMS (ESI, m z): 410 [M+H]⁺.

To a stirred solution ofN-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-N,N-dimethylmethanimidamide(950.00 mg, 2.315 mmol) in ethanol (10 mL) was added ethylenediamine(626.19 mg, 10.419 mmol) dropwise at rt. The resulting mixture wasstirred overnight at 70° C. and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography withCH₂Cl₂/methanol (49/1) to afford6-(4-amino-2,6-dichlorophenoxy)-4-(3,3-dimethylazetidin-1-yl)-2H-pyridazin-3-one(420 mg, 49.53%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.59(s, 1H), 6.60 (s, 2H), 5.74 (s, 1H), 5.53 (s, 2H), 3.86 (br, 4H), 1.24(s, 6H). LCMS (ESI, m z): 355 [M+H]⁺.

To a stirred solution of6-(4-amino-2,6-dichlorophenoxy)-4-(3,3-dimethylazetidin-1-yl)-2H-pyridazin-3-one(250.00 mg, 0.706 mmol) in HCl (8.0 mL), acetic acid (22 mL) and water(16 mL) was added sodium nitrite (102.0 mg, 1.483 mmol) in water (2 mL),dropwise at 0° C. The resulting mixture was stirred for 45 min at 0° C.Ethyl N-(2-cyanoacetyl)carbamate (165.0 mg, 1.059 mmol) in water (52 mL)and pyridine (8 mL) was stirred for 10 min at 0° C. Put the abovesolution to this mixture and the resulting mixture was stirred for 1 hat 0° C. The resulting mixture was filtered, the filter cake was washedwith water (2×10 mL) and dried under IR lamp to afford ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-(3,3-dimethylazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(300 mg, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.07-12.10 (m, 1H), 11.66 (s, 1H), 10.90 (s, 1H), 7.93 (s, 2H), 5.83(s, 1H), 4.15-4.22 (m, 2H), 3.61-4.01 (m, 4H), 1.26 (s, 9H). LCMS (ESI,m z): 522 [M+H]⁺.

To a stirred mixture of ethyl(2-cyano-2-(2-(3,5-dichloro-4-((5-(3,3-dimethylazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(300 mg, 0.574 mmol) in DMA (8 mL) was added KOAc (225.47 mg, 2.297mmol) in portions at rt. The resulting mixture was stirred for 6 h at110° C. and quenched by water (15 mL) at rt. The mixture was extractedwith ethyl acetate (3×40 mL) and the organic layers were combined,washed with brine (2×40 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(300 mg, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (s,1H), 11.70 (s, 1H), 7.73 (s, 2H), 5.91 (s, 1H), 3.92 (br, 4H), 1.27 (s,6H). LCMS (ESI, m z): 476 [M+H]⁺.

To a stirred mixture of2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(180.00 mg, 0.378 mmol) in methanol (4 mL) was added NaOH (8 mL, 2M)dropwise at rt. The resulting mixture was stirred for 30 min at 55° C.and diluted with water (30 mL) at rt. The resulting mixture wasextracted with EA (3×50 mL) and the organic layers were combined, werewashed with brine (2×40 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (180 mg, crude) as a yellow solid. LCMS (ESI, m z): 495 [M+H]⁺.

To a stirred mixture of2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (180.00 mg, 0.363 mmol) and triethylamine (147.11 mg, 1.454 mmol)in t-butanol (5 mL) was added diphenylphosphoryl azide (300.05 mg, 1.090mmol) dropwise at rt. The resulting mixture was stirred for overnight at85° C. The resulting mixture was concentrated under reduced pressure.The residue was extracted with EA (3×40 mL) and the organic layers werecombined, washed with brine (2×30 mL), dried over anhydrous sodiumsulfate, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with dichloromethane/methanol (24/1)to afford t-butylN-[2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(48 mg, 18%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 12.79 (s, 1H),11.13 (s, 1H), 7.59 (s, 1H), 7.55 (s, 2H), 5.72 (s, 1H), 4.02 (s, 4H),1.51 (s, 9H), 1.25 (s, 6H). LCMS (ESI, m z): 566 [M+H]⁺.

To a stirred solution of t-butylN-[2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(38.00 mg, 0.067 mmol) in CH₂Cl2 (5 mL) was added TFA (1 mL) dropwise atrt. The resulting mixture was stirred for 2 h at rt and concentratedunder reduced pressure. The residue was purified by prep-HPLC with thefollowing conditions (Column: XBridge Prep Phenyl OBD, 19×150 mm Sum 13nm; Mobile Phase A: water (10 MMOL/L NH₄CO₃+0.1% NH₄OH), Mobile Phase B:Acetonitrile; Flow rate:25 mL/min; Gradient:20 B to 39 B in 8 min; 254nm; RT1:6.52) to afford6-amino-2-(3,5-dichloro-4-[[5-(3,3-dimethylazetidin-1-yl)-6-oxo-1H-pyridazin-3-yl]oxy]phenyl)-4H-1,2,4-triazine-3,5-dione(8.1 mg, 26%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.67 (br,2H), 7.79 (s, 2H), 6.44 (s, 2H), 5.87 (s, 1H), 3.77 (br, 4H), 1.27 (s,6H). LCMS (ESI, m z): 466 [M+H]⁺.

Example 91: Synthesis of Compound 160

A 500 mL autoclave was charged with 3-chloro-6-methoxypyridazine (50.00g, 345.877 mmol), Pd(dppf)Cl₂ (15.18 g, 20.753 mmol), triethylamine(12.25 g, 121.057 mmol) and methanol (150 mL), and CO (30 atm). Thereaction was stirred at 60° C. for 3 days. The resulting solution wasconcentrated under reduced pressure to get the residue. The residue waschromatographed on a silica gel column with PE/EA (3/1) to get methyl6-methoxypyridazine-3-carboxylate (16.4 g, 27%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.10 (d, J=9.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 4.25(s, 3H), 4.06 (s, 3H). LCMS (ESI, m z): 169 [M+H]⁺.

To a solution of methyl 6-methoxypyridazine-3-carboxylate (16.40 g,97.531 mmol) in methanol (55 mL) and THF (275 mL) was added NaBH₄ (11.07g, 292.592 mmol) and CaCl₂) (10.82 g, 97.531 mmol) in portions. Thereaction was stirred at rt for 1 h and quenched with water andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column with methanol/CH₂Cl₂ (1/17) to get(6-methoxypyridazin-3-yl)methanol (10.5 g, 73%) as a brown oil. ¹H NMR(300 MHz, methanol-d₄) δ 7.24 (d, J=9.0 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H),4.79 (s, 2H), 4.10 (s, 3H). LCMS (ESI, m z): 141 [M+H]⁺.

To a solution of (6-methoxypyridazin-3-yl)methanol (10.20 g, 72.783mmol) in dichloromethane (500 mL) was added Dess-Martin periodinane(43.22 g, 101.897 mmol). The reaction was stirred at rt for 16 h andquenched with water (200 mL). The resulting solution was extracted withCH₂Cl₂ (3×200 mL) and the organic layers were combined, washed withbrine (2×100 mL), dried over anhydrous sodium sulfate, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure. The residue was chromatographed on a silica gel column withEA/PE (1/3) to provide 6-methoxypyridazine-3-carbaldehyde (7.5 g, 67%)as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 10.27 (s, 1H), 7.97 (d,J=9.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.29 (s, 3H). LCMS (ESI, m/z):139 [M+H]⁺.

To a solution of 2,2,6,6-tetramethylpiperidine (6.83 g, 48.332 mmol) inTHF (100 mL) was added n-butyllithium (17.7 mL, 2.5M in hexane, 44.304mmol) at −85° C. under nitrogen and then the solution was allowed towarm to 0° C. and stirred for 30 min. Then the solution was cooled to−85° C. and a solution of 3,6-dichloropyridazine (6 g, 40.277 mmol) inTHF (25 mL) was added. The reaction was stirred at −85° C. for 30 minand a solution of 6-methoxypyridazine-3-carbaldehyde (6.12 g, 44.304mmol) in THF (25 mL) was added. The resulting solution was stirred at−85° C. for 1 h and quenched with NH₄Cl (aq., 100 mL). The resultingsolution was extracted with EA (3×100 mL) and the organic layers werecombined, washed with brine (1×100 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column with EA/PE (2/3) to get thecrude product. The crude product was purified by C18 column(CH₃CN/water=1/3) to provide(3,6-dichloropyridazin-4-yl)(6-methoxypyridazin-3-yl)methanol (2.38 g,18.52%) as a brown solid. ¹H NMR (300 MHz, CDCl₃) δ 7.94 (s, 1H), 7.52(d, J=9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.27 (s, 1H), 4.76 (b, 1H),4.29 (s, 3H). LCMS (ESI, m z): 287 [M+H]⁺.

To a solution of(3,6-dichloropyridazin-4-yl)(6-methoxypyridazin-3-yl)methanol (4 g,13.93 mmol) in CH₂Cl2 (160 mL) was added 2,6-lutidine (5.9718 g, 55.73mmol) and sulfurous dichloride (3.3151 g, 27.86 mmol). The reaction wasstirred at rt for 16 h and quenched with water (100 mL). The resultingsolution was extracted with CH₂Cl₂ (3×100 mL) and the organic layerswere combined, washed with brine (2×100 mL), dried over anhydrous sodiumsulfate, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was chromatographed ona silica gel column with EA/PE (1/3) to get3,6-dichloro-4-[chloro(6-methoxypyridazin-3-yl)methyl]pyridazine (2.6 g,61.2%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.65 (d,J=9.0 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.43 (s, 1H), 4.16 (s, 3H). LCMS(ESI, m z): 305 [M+H]⁺.

To a solution of3,6-dichloro-4-[chloro(6-methoxypyridazin-3-yl)methyl]pyridazine (2.600g, 8.510 mmol) in toluene (104 mL) was added tributyltin hydride (4954mg, 17.019 mmol) and 2,2′-azobis(2-methylpropionitrile) (279.47 mg,1.702 mmol). The reaction was stirred at 100° C. for 16 h and quenchedwith water (100 mL). The mixture was extracted with ethyl acetate (3×100mL) and the organic layers were combined, washed with brine (100 mL),dried over anhydrous sodium sulfate, the solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column with EA/PE (1/2) toget 3,6-dichloro-4-[(6-methoxypyridazin-3-yl)methyl]pyridazine (1.9 g,76%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.55 (s, 1H), 7.41 (d,J=6.0 Hz, 1H), 7.05 (d, J=6.0 Hz, 1H), 4.35 (s, 2H), 4.16 (s, 3H). LCMS(ESI, m/z): 271 [M+H]⁺.

To a solution of3,6-dichloro-4-[(6-methoxypyridazin-3-yl)methyl]pyridazine (1.100 g,4.058 mmol) and 4-amino-2,6-dichlorophenol (866.74 mg, 4.869 mmol) inDMSO (22 mL) was added K₂CO₃ (1401.94 mg, 10.144 mmol). The reaction wasstirred at 90° C. for 8 h and quenched with water (100 mL). The mixturewas extracted with EA (3×100 mL) and the organic layers were combined,washed with brine (1×50 mL), dried over anhydrous sodium sulfate, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn with EA/PE (1/2) to afford3,5-dichloro-4-([6-chloro-5-[(6-methoxypyridazin-3-yl)methyl]pyridazin-3-yl]oxy)aniline(430 mg, 25%) as brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.68-7.71 (m,2H), 7.26 (d, J=9.0 Hz, 1H), 6.72 (s, 2H), 4.97 (b, 2H), 4.40 (s, 2H),3.99 (s, 3H). LCMS (ESI, m/z): 412 [M+H]⁺.

To a solution of3,5-dichloro-4-([6-chloro-5-[(6-methoxypyridazin-3-yl)methyl]pyridazin-3-yl]oxy)aniline(435.00 mg, 1.054 mmol) in water (32 mL), conc. HCl (12 mL) and aceticacid (36 mL) was added sodium nitrite (152.73 mg, 2.214 mmol) in water(5 mL) dropwise at 0° C. After the addition, the reaction was stirred at0° C. for 45 min. Then the reaction mixture was added to a solution ofethyl N-(2-cyanoacetyl)carbamate (246.89 mg, 1.581 mmol) in water (32mL) and pyridine (14 mL) at 0° C. quickly. The resulting mixture wasstirred at 0° C. for 1 h and filtered. The filter cake was dried underIR lamp to get ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((6-methoxypyridazin-3-yl)methyl)pyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate (410 mg, 62.01%) as a brown yellow solid. LCMS (ESI, mz): 579 [M+H]⁺.

To a solution of ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((6-methoxypyridazin-3-yl)methyl)pyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(410.00 mg, 0.707 mmol) in acetic acid (10 mL) was added sodium acetate(290.3 mg, 3.54 mmol). The reaction was stirred at 105° C. for 4 h andcooled to rt. The reaction was poured into water (100 mL) and filtered.The filter cake was dissolved in DMF and purified by C18 column(CH₃CN/water=2/3) to get2-[3,5-dichloro-4-([5-[(6-methoxypyridazin-3-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(270 mg, 67%) as a brown solid. ¹H NMR (300 MHz, methanol-d₄) δ7.83-7.87 (m, 2H), 7.78 (s, 2H), 7.56 (s, 1H), 4.15 (s, 3H), 2.05 (s,2H). LCMS (ESI, m z): 515 [M+H]⁺.

A solution of2-[3,5-dichloro-4-([5-[(6-methoxypyridazin-3-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(160.00 mg, 0.311 mmol) in acetic acid (5 mL) and conc. HCl (aq. 2.5 mL)was stirred at 105° C. for 3 h. The pH value of the reaction mixture wasadjusted to 10 with NaHCO₃ (sat., aq.) and extracted with EA (2×20 mL)and the organic layers were discarded. The pH value of the aqueouslayers was adjusted to 4 with conc. HCl and extracted withisopropanol/CHCl₃ (1/3) (2×50 ml). The organic layers were combined,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to get2-[3,5-dichloro-4-([5-[(6-hydroxypyridazin-3-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (120 mg, 66.8%) as a brown solid. LCMS (ESI, m z): 520 [M+H]⁺.

To a solution of2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (110 mg, 0.211 mmol) in t-butanol (4 mL) was added DPPA (174.57 mg,0.634 mmol) and triethylamine (85.58 mg, 0.846 mmol). The reaction wasstirred at 80° C. for 16 h and concentrated under reduced pressure. Theresidue was dissolved in EA (50 mL). The resulting mixture was washedwith sodium bicarbonate solution (3×30 mL) and brine. The combinedorganic layers were dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure toafford t-butylN-[2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(60 mg, 38%) as a white solid. LCMS (ESI, m z): 591 [M+H]⁺.

To a solution of t-butylN-[2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(60 mg, 0.101 mmol) in CH₂Cl₂ (5 mL) was added TFA (2 mL). The reactionwas stirred at rt for 2 h and concentrated under reduced pressure. Theresidue was purified by Pre-HPLC(Column: XBridge Shield RP18 OBD Column,19×250 mm, 10 μm; Mobile Phase A:Water (10 MMOL/L NH₄HCO₃+0.1% NH₃.H₂O),Mobile Phase B: CH₃CN; Flow rate:25 mL/min; Gradient:10 B to 35 B in 7min; 220 nm; RT1:6.35) to get6-amino-2-[3,5-dichloro-4-([6-oxo-5-[(6-oxo-1H-pyridazin-3-yl)methyl]-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dione(5.7 mg, 11.32%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (s,2H), 7.56 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 6.88 (d, J=9.6 Hz, 1H), 6.48(s, 2H), 3.83 (s, 2H). LCMS (ESI, m/z): 491 [M+H]⁺.

Example 92: Synthesis of Compound 161

Potassium t-butoxide (43.19 g, 384.869 mmol) was added to6-methylpyridin-3-ol (40.00 g, 366.542 mmol) in THF (1.6 L) at 0° C. Themixture was stirred at rt for 30 min. CH₃I (54.63 g, 384.869 mmol) wasadded dropwise at 0° C., and stirring was continued at rt for overnight.Water (500 mL) was added and the mixture was evaporated to half itsvolume and extracted with ethyl acetate (3×500 mL). The combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column with EA/PE (1/3) togive 5-methoxy-2-methylpyridine (17.5 g, 36.8%). ¹H NMR (300 MHz,Methanol-d₄) δ 8.09 (d, J=3.0 Hz, 1H), 7.33 (dd, J=8.6, 3.0 Hz, 1H),7.22 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 2.46 (s, 3H). LCMS (ESI, m z): 124[M+H]⁺.

To a solution of 2,2,6,6-tetramethylpiperidine (13.76 g, 97.438 mmol) inTHE (75 mL) was added n-butyllithium (39 mL, 2.5M in hexane, 97.438mmol) at −75° C. under nitrogen and then the solution was allowed towarm to 0° C. and stirred for 30 min. Then the solution was cooled to−75° C. and a solution of 5-methoxy-2-methylpyridine (10.00 g, 81.198mmol) in THF (75 mL) was added. The reaction was stirred at −75° C. for30 min and a solution of 3,4,6-trichloropyridazine (17.87 g, 97.438mmol) in THF (50 mL) was added. The resulting solution was stirred at−75° C. for 1 h. The reaction was quenched with NH₄C₁ (aq., 100 mL). Theresulting solution was extracted with EA (3×300 mL) and the organiclayers were combined, washed with brine (1×100 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column with EA/PE (1/3) toget 3,6-dichloro-4-[(5-methoxypyridin-2-yl)methyl]pyridazine (3.2 g,13.8%) as a light brown solid. ¹H NMR (300 MHz, methanol-d₄) δ 8.19-8.20(m, 1H), 7.67 (s, 1H), 7.33-7.48 (m, 2H), 4.26 (s, 2H), 3.89 (s, 3H).LCMS (ESI, m/z): 270 [M+H]⁺.

To a solution of3,6-dichloro-4-[(5-methoxypyridin-2-yl)methyl]pyridazine (3.20 g, 11.847mmol) in DMSO (90 mL) was added 4-amino-2,6-dichlorophenol (2.53 g,14.216 mmol) and potassium carbonate (4.91 g, 35.541 mmol). The mixturewas stirred at 90° C. for 2 h and quenched with water (100 mL). Theresulting solution was extracted with EA (3×200 mL) and the organiclayers were combined, washed with brine, dired over anhyrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a C₁₈ column with acetonitrile/water (2/3) to get3,5-dichloro-4-([6-chloro-5-[(5-methoxypyridin-2-yl)methyl]pyridazin-3-yl]oxy)aniline(1.51 g, 165.13%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (s,1H), 7.55 (s, 1H), 7.39-7.52 (m, 2H), 6.70 (s, 2H), 4.80 (br, 2H), 4.26(s, 2H), 3.83 (s, 3H). LCMS (ESI, m/z): 411 [M+H]⁺.

To a solution of3,5-dichloro-4-([6-chloro-5-[(5-methoxypyridin-2-yl)methyl]pyridazin-3-yl]oxy)aniline(1.50 g, 3.635 mmol) in acetic acid (130 mL), concentrated HCl (45 mL)and water (100 mL) was added sodium nitrite solution (0.53 g, 7.633mmol) in water (10 mL) dropwise at 0° C. Then the reaction was stirredat 0° C. for 45 min. Then the reaction mixture was added to the mixtureof ethyl N-(2-cyanoacetyl)carbamate (0.85 g, 5.452 mmol) in pyridine (50mL) and water (100 mL) at 0° C. quickly. The resulting mixture wasstirred for 30 min at 0° C. The precipitated solids were collected byfiltration and washed with water and PE (50 mL) to afford ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((5-methoxypyridin-2-yl)methyl)pyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(1.03 g, 45.5%) as a yellow solid. LCMS (ESI, m z): 578 [M+H]⁺.

To a solution of ethyl(2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-((5-methoxypyridin-2-yl)methyl)pyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate(1.00 g, 1.785 mmol) in acetic acid (30 mL) was added sodium acetate(0.73 g, 8.923 mmol). The mixture was stirred at 105° C. for 3 h andquenched with water (100 mL). The precipitated solids were collected byfiltration and washed with water and PE (20 mL). The residue waschromatographed on a C₁₈ column with CH₃CN/water (2/3) to get2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(200 mg, 20.27%) as a brown solid. LCMS (ESI, m z): 514 [M+H]⁺.

To a solution of2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carbonitrile(200.00 mg, 0.390 mmol) in acetic acid (4 mL) was added concentratedhydrochloric acid (2 mL). The mixture was stirred at 105° C. for 3 h.The pH of the reaction mixture was adjusted to 10 with NaHCO₃ (sat.,aq.) and extracted with EA (2×20 mL) and the organic layers werediscarded. The pH value of the aqueous layers was adjusted to 4 withconcentrated hydrochloride acid and extracted withisopropanol/chloroform (1/3) (2×50 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, the solids were removedby filtration and the filtrate was concentrated under reduced pressureto afford2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (200 mg, 77.15%) as a yellow solid. LCMS (ESI, m z): 533 [M+H]⁺.

To a solution of2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazine-6-carboxylicacid (200 mg, 0.375 mmol) in t-butyl alcohol (8 mL) was added DPPA(309.63 mg, 1.125 mmol), triethylamine (151.80 mg, 1.500 mmol). Themixture was stirred at 85° C. overnight and concentrated under reducedpressure. The residue was dissolved in EA (50 mL). The resulting mixturewas washed with sodium bicarbonate solution (3×30 mL) and brine. Thecombined organic layers were dried over anhydrous sodium sulfate. Thesolids were removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was chromatographed on a C18 columnwith CH₃CN/water (1/2) to afford t-butylN-[2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(112 mg, 47.38%) as a brown solid. LCMS (ESI, m z): 604 [M+H]⁺.

To a solution of t-butylN-[2-[3,5-dichloro-4-([5-[(5-methoxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-3,5-dioxo-4H-1,2,4-triazin-6-yl]carbamate(50.00 mg, 0.083 mmol) in CH₂Cl2 (3 mL) was added BBr3 (414.50 mg, 1.655mmol) at 0° C. The mixture was stirred at rt for 2 days. The reactionmixture was quenched with methanol and concentrated under reducedpressure. The residue was purified by preparatory HPLC (Column: XSelectCSH Prep C18 OBD, 19×250 mm, 5 μm; Mobile Phase A: Water (10 MMOL/LNH₄CO₃+0.1% NH₄OH), Mobile Phase B: CH₃CN; Flow rate:25 mL/min;Gradient:10 B to 30 B in 8 min; 254 nm; RT1:6.65) to get6-amino-2-[3,5-dichloro-4-([5-[(5-hydroxypyridin-2-yl)methyl]-6-oxo-1H-pyridazin-3-yl]oxy)phenyl]-4H-1,2,4-triazine-3,5-dione(8 mg, 19.41%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (br,2H), 9.82 (br, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.85 (s, 2H), 7.13-7.28 (m,3H), 6.49 (br, 2H), 3.89 (s, 2H). LCMS (ESI, m/z): 490 [M+H]⁺.

Example 93: Synthesis of Compound 162

A mixture of5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine(200 mg, 322.27 umol, 90% purity),6-bromo-2-methyl-1,2,4-triazine-3,5-dione (69.71 mg, 338.38 umol), K₂CO₃(89.08 mg, 644.54 umol) and palladium; triphenylphosphane (74.48 mg,64.45 umol) in dioxane (8 mL) and H₂O (1.6 mL) was stirred at 110° C.for 12 hr under N₂. The reaction mixture was cooled down, diluted withH₂O (30 mL) and extracted with EA (30 mL×2). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by silica gel chromatography (Eluent of 0-50% EA/PE) togive6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-2-methyl-1,2,4-triazine-3,5-dione(96 mg, 106.73 umol, 33.12% yield, 62% purity) as a yellow solid.

To a solution of6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-2-methyl-1,2,4-triazine-3,5-dione(96 mg, 172.15 umol) in THE (8 mL) was added TBAF (1 M, 1.38 mL) at 20°C. After the addition, the mixture was stirred at 65° C. for 12 h. LCMSshowed the starting material was consumed completely and 29% desiredmass was detected. The reaction mixture was diluted with sat. aq. NH₄C₁(120 mL) and extracted with EA (30 mL×2). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC [Column: Phenomenex luna C18 80×40 mm×3 um;mobile phase: from 15% CH₃CN in water (0.05% HCl) to 45% CH₃CN in water(0.05% HCl)] to give 6-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-2-methyl-1,2,4-triazine-3,5-dione]0.6-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-2-methyl-1,2,4-triazine-3,5-dione(14.07 mg, 33.87 umol, 19.68% yield, 97.13% purity) as a white solid.

Example 94: Synthesis of Compounds 163 and 164

6-Amino-2-(3,5-dichloro-4-((6-oxo-5-(1-phenylethyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dioneSynthesisof 6-bromo-4-isopropyl-1,5-naphthyridin-2(1H)-one was synthesized usinga method analogous to that described for the synthesis of6-amino-2-(3,5-dichloro-4-((5-(2-fluoro-3-methylphenyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dionewhere (1-phenylvinyl)boronic acid was employed instead of(2-fluoro-3-methylphenyl)boronic acid.

The crude product (200 mg) was purified by preparative HPLC (Column:CHIRALPAK IE-3, 4.6×50 mm, 3 μm, Hexane (0.1% TFA): EtOH=55:45, flowrate:1 mL/min) to provide the first eluting enantiomer (Rt: 2.340 min),compound 163 (37.9 mg, 19.69%), as a white solid. And the second elutingisomer (Rt: 2.903 min), compound 164 (41.5 mg, 21.65%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.24-12.27 (m, 2H), 7.85 (s, 2H), 7.51 (s,1H), 7.31-7.35 (m, 4H), 7.21-7.26 (m, 1H), 6.52 (s, 2H), 4.27-4.33 (m,1H), 1.55 (d, J=7.2 Hz, 3H). LCMS (ESI, m z): 487 [M+H]⁺.

Example 95: Synthesis of Compounds 165 and 166

A chiral separation was performed on6-amino-2-(4-((5-(bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-1,2,4-triazine-3,5(2H,4H)-dioneto afford compounds 165 (Rt: 2.845 min on chiral HPLC) and 166 (Rt:3.697 min on chiral HPLC) (Chiral HPLC conditions: column name:(R,R)-WHELK-01 4.6×50 mm 3.5 um, mobile phase:Hex (0.1%DEA):ethanol=70:30, temperature: 25° C., flow 1.000 mL/min, instrument:Agilent 1260). ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (br, 2H), 7.84 (s, 2H),7.19-7.39 (m, 5H), 6.50 (s, 2H), 4.71 (s, 1H), 3.63-3.69 (m, 1H),3.19-3.24 (m, 1H).

Example 96: Synthesis of Compound 171

A mixture of5-[[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridine(320 mg, 0.516 mmol, 90% purity), 6-bromo-2H-1,2,4-triazine-3,5-dione(148.48 mg, 0.773 mmol), K₂CO₃ (142.53 mg, 1.03 mmol) and palladium;triphenylphosphane (119.17 mg, 0.103 mmol) in dioxane (10 mL) and H₂O (1mL) was stirred at 100° C. for 12 h under N₂. The reaction mixture wasdiluted with H₂O (20 mL) and extracted with EA (20 mL×2). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give crude product, which waspurified by flash silica gel chromatography (Eluent of 0˜50% EA/PE) togive6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-2H-1,2,4-triazine-3,5-dione(246 mg, 0.453 mmol, 88% yield) as a colorless oil. LCMS (ESI, m z): 544[M+H]⁺.

To a solution of6-[4-[[3-isopropyl-1-(p-tolylsulfonyl)pyrrolo[3,2-b]pyridin-5-yl]methyl]-3,5-dimethyl-phenyl]-2H-1,2,4-triazine-3,5-dione(200 mg, 0.368 mmol) in THF (8 mL) was added TBAF (1 M, 1.84 mL) at 20°C. The mixture was stirred at 65° C. for 12 h. The reaction mixture wasdiluted with H₂O (50 mL), extracted with EA (100 mL). The organic layerwas washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by prep-HPLC[Column: Phenomenex luna C18 80×40 mm×3 um; mobile phase: from 10% CH₃CNin water (0.05% HCl) to 40% CH₃CN in water (0.05% HCl)] then dissolvedin EA (20 mL), washed with NH₄C₁ (sat., aq., 20 mL), brine (20 mL) andconcentrated to afford6-[4-[(3-isopropyl-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl]-3,5-dimethyl-phenyl]-2-methyl-1,2,4-triazine-3,5-dione(5 mg, 12.84 umol, 3.5% yield, 100% purity) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.43 (d, J=1.8 Hz, 1H), 12.04 (s, 1H), 10.80 (brs, 1H), 7.58-7.52 (m, 3H), 7.29 (d, J=1.6 Hz, 1H), 6.65 (d, J=8.4 Hz,1H), 4.23 (s, 2H), 3.24-3.16 (m, 1H), 2.37 (s, 6H), 1.33 (d, J=6.9 Hz,6H).

Example 97: Synthesis of 6-bromo-4-isopropyl-1,5-naphthyridin-2(1H)-one

To a solution of 2,6-dibromopyridin-3-amine (30 g, 119.09 mmol) in DCM(500 mL) was added Et₃N (36.15 g, 357.27 mmol, 49.73 mL) and2,2-dimethylpropanoyl chloride (28.72 g, 238.18 mmol, 29.31 mL) at 0°C., and the mixture was stirred at 15° C. for 12 h. The mixture wasquenched by sat. aq. NH₄C₁ (sat., aq., 100 mL), extracted with DCM (200mL×3). The combined organic layers were washed with brine (100 mL×2),dried over MgSO₄, filtered and concentrated to give a residue, which waspurified by silica gel chromatography (Eluent of 0˜20% EA/PE) to giveN-(2,6-dibromopyridin-3-yl)pivalamide (41.4 g, crude) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.71(d, J=8.3 Hz, 1H), 1.24 (s, 9H).

To a solution of N-(2,6-dibromopyridin-3-yl)pivalamide (21 g, 62.50mmol) in toluene (300 mL) was added dropwise n-BuLi (2.5 M, 62.50 mL) at−70° C. under N₂, the mixture was stirred at −70° C. for 2 h. Then tothe mixture was added 2-methylpropanal (9.01 g, 124.99 mmol, 11.41 mL),the resulting mixture was stirred at −70° C. for 2 h. The mixture wasquenched by sat. aq. NH₄Cl (60 mL) at −70° C., then warmed to 10° C.,diluted with H₂O (200 mL) and extracted with EA (200 mL×3). The combinedorganic layers were washed with brine (300 mL), dried over anhydrousNa₂SO₄, filtered and concentrated to give a residue, which was purifiedby flash silica gel chromatography (0˜10% EA in PE) to affordN-(6-bromo-2-(1-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (13 g,37.71 mmol, 30.17% yield, 95.5% purity) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.50 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.8Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 4.45 (dd, J=4.6, 6.8 Hz, 1H), 2.06-1.93(m, 1H), 1.21 (s, 9H), 0.93 (d, J=6.6 Hz, 3H), 0.77 (d, J=6.8 Hz, 3H).

To a solution ofN-(6-bromo-2-(1-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (13 g,39.49 mmol) in DCM (350 mL) was added Dess-Martin (50.24 g, 118.46 mmol,36.67 mL) in portions at 20° C. After the addition, the mixture wasstirred at 20° C. for 3 h. LCMS showed the starting material wasconsumed completely and 47.3% of desired product formed under 220 nm.The mixture was quenched by addition of sat. aq. Na₂SO₃ (100 mL) andsat. aq. NaHCO₃(200 mL), extracted with DCM (100 mL×3). The combinedorganic layers were washed with brine (200 mL), dried over anhydrousMgSO₄, filtered and concentrated to give a residue, which was purifiedby flash silica gel chromatography (EA in PE=0-10%) to giveN-(6-bromo-2-isobutyrylpyridin-3-yl)pivalamide (11 g, 33.48 mmol, 84.80%yield, 99.6% purity) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ11.59 (s, 1H), 8.94 (d, J=9.0 Hz, 1H), 7.89 (d, J=9.0 Hz, 1H), 4.02(spt, J=6.9 Hz, 1H), 1.26 (s, 9H), 1.13 (d, J=6.9 Hz, 6H).

To a solution of LDA (2 M, 35.30 mL) in THF (250 mL) was added t-butylacetate (8.20 g, 70.60 mmol, 9.47 mL) at −70° C., the mixture wasstirred at −70° C. for 30 min. Then to the mixture was addedN-(6-bromo-2-isobutyrylpyridin-3-yl)pivalamide (11 g, 33.62 mmol) in THF(50 mL) at −70° C., the resulting mixture was stirred at −70° C. for 1h. The mixture was quenched with sat. aq. NH₄Cl (100 mL) at −70° C. Thenwarmed to 20° C., diluted with H₂O (100 mL) and extracted with EA (100mL×3). The combined organic layers were washed with brine (200 mL),dried over anhydrous MgSO₄, filtered and concentrated to give a residue,which was purified by flash silica gel chromatography (0˜10% EA in PE)to afford t-butyl3-(6-bromo-3-pivalamidopyridin-2-yl)-3-hydroxy-4-methylpentanoate (14.92g, 26.55 mmol, 78.98% yield, 78.9% purity) as a yellow oil.

The reaction was set up in 4 batches. t-Butyl3-(6-bromo-3-pivalamidopyridin-2-yl)-3-hydroxy-4-methylpentanoate (2 g,3.56 mmol, 78.9% pure) and HBr (18.42 mmol, 5 mL, 20%) were taken upinto a microwave tube in dioxane (1 mL). The sealed tube was heated at160° C. for 25 min under microwave irradiation. The combined reactionmixture was diluted with H₂O (100 mL) and EA (100 mL). The suspensionwas filtered, and the filtrate was extracted with EA (100 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overanhydrous MgSO₄, filtered and concentrated to give a residue, which waspurified by flash silica gel chromatography (0˜70% EA in PE) to give6-bromo-4-isopropyl-1,5-naphthyridin-2(1H)-one (4.36 g, 15.64 mmol,60.60% yield, 95.8% purity) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.89 (br s, 1H), 7.75-7.66 (m, 1H), 7.60 (d, J=8.6 Hz, 1H), 6.60 (s,1H), 3.70-3.56 (m, 1H), 1.23 (d, J=7.0 Hz, 6H).

Example 98: Methodology for LCMS

1. Description of LCMS Conditions

Several different conditions were used to assess the purity, retentiontime and [M+H]⁺ or [M−H]⁻ of the compounds disclosed herein using LCMSmethods. The conditions are listed in Table 1, below. All data wereobtained using a Shimadzu LCMS-2020 instrument except when noteddifferently. For all conditions, column temperature was 40° C. and runtime was 3 m, except when noted differently. Flow is reported in unitsof mL/min. “C” is the number indicator for the listed LCMS condition,which is then referenced in Table 2, below.

TABLE 1 C Column Mobile phase Gradient Flow  1 Ascentis Express C18 A:H₂O + 0.05% TFA From 95% A to 5% A in 1.99 1.5 (2.7 μm, 3.0 × 50 mm) B:CH₃CN + 0.05% TFA min, held for 0.6 min, to 95% A column temp: 40° C. in0.15 min, held for 0.25 min  2 ACE Excel 3 Super A: H₂O + 5 mM From 90%A to 5% A in 2.09 1.2 (3.0 μm, 3.0x50 mm) NH₄HCO₃ min, held for 0.6 min,to 90% A column temp: 40° C. B: CH₃CN in 0.05 min, held for 0.25 min  3YMC-Triart C18 A: H₂O + From 90% A to 5% A in 1.89 1.5 (3.0 μm, 3.0 × 50mm) 0.04% NH₄OH min, held for 0.8 min, to 90% A column temp: 40° C. B:CH₃CN in 0.05 min, held for 0.25 min  4 Poroshell HPH-C18 A: 6.5 mM From90% A to 5% A in 1.99 1.2 (2.7 μm, 3.0 × 50 mm) NH₄HCO₃ +NH₃H₂O min,held for 0.6 min, to 90% A column temp: 40° C. B: CH₃CN in 0.15 min,held for 0.25 min  5 HALO C18 A: H₂O + 0.05% TFA From 95% A to 50% A in1.79 1.5 (2.0 μm, 3.0 × 30 mm) B: CH₃CN + 0.05% TFA min, to 5% A in 0.7min, held column temp: 40° C. for 0.3 min, to 95% A in 0.01 min, heldfor 0.19 min. Runtime 3 min  5A HALO C18 From 95% A to 0% A in (2.7 μm,3.0 × 50 mm), 1.99 min, held for 0.7 min, to column temp.: 40° C. 95% Ain 0.05 min, held for 0.15 min. Runtime 2.9 min  5B (2.7 μm, 3.0 × 50mm), From 70% A to 5% A in column temp.: 45° C. 3.99 min, held for 0.8min, to 95% A in 0.2 min, held for 0.2 min. Runtime 5.2 min  5C From 95%A to 45% A in 1.5 2.99 min, to 0% A in 1 min, held for 0.6 min, to 95% Ain 0.1 min, held for 0.5 min. Runtime 5.2 min  6 Shim-pack XR-ODS From95% A to 0% A in 1.99 1.2 (2.2 μm, 3.0 × 50 mm) min, held for 0.7 min,to 95% A column temp.: 40° C. in 0.05 min, held for 0.25 min  7 XselectCSH C18 A: H₂O/0.1% FA From 95% A to 5% A in 2.09 1.2 (2.5 μm, 3.0 × 50mm) B: CH₃CN/0.1% FA min, held for 0.6 min, to 95% A column temp.: 40°C. in 0.05 min, held for 0.25 min  8 CORTECS C18 A: H₂O + 0.05% TFA From95% A to 0% A in 1.99 1.0 (2.7 μm, 2.1 × 50 mm) B: CH₃CN + 0.05% TFAmin, held for 0.8 min, to 95% A column temp.: 40° C. in 0.1 min, heldfor 0.1 min  9 Ascentis Express C18 A: H₂O + 0.05% TFA From 95% A to 0%A in 1.5 (2.7 μm, 3.0 × 50 mm) B: CH₃CN + 0.05% TFA 1.99 min, held for0.8 min, to column temp.: 40° C. 95% A in 0.1 min, held for 0.1 min 10From 95% A to 5% A in 1.0 1.99 min, held for 0.7 min, to 95% A in 0.1min, held for 0.2 min 11 Ascentis Express C18 A: H₂O + 0.05% TFA From95% A to 60% A in 1.5 (2.7 μm, 3.0 × 50 mm), B: CH₃C + 0.05% TFA 3.19min, to 0% A in 0.8 min, column temp.: 45° C. held for 0.6 min, to 95% Ain 0.1 min, held for 0.5 min. Runtime: 5.2 min 12 Kinetex 2.6 μm A:H₂O + 5 mM From 90% A to 5% A in 1.99 1.2 EVO C18 100A NH₄HCO₃ min, heldfor 0.6 min, to 90% A (2.6 μm, 3.0 × 50 mm), B: CH₃CN in 0.15 min, heldfor 0.10 min. column temp.: 40° C. Runtime: 2.85 min  12A From 90% A to5% A in 1.99 min, held for 0.7 min, to 90% A in 0.05 min, held for 0.10min. Runtime: 2.85 min 13 Ascentis Express C18 A: H₂O + 0.05% TFA From95% A to 40% A in 3.19 1.5 (2.7 μm, 3.0 × 50 mm), B: CH₃CN + 0.05% TFAmin, to 5% A in 0.9 min, held column temp.: 40° C. for 0.9 min, to 95% Ain 0.1 min, held for 0.2 min. Runtime: 5.3 min  13B From 95% A to 30% Ain 3.59 min, to 5% A in 0.6 min, held for 0.8 min, to 95% A in 0.1 min,held for 0.2 min  14A/ Xtimate C18 A: H₂O (4L) + From 90% A to 20% A in3 14A: 0.8 B/F 2.1 × 30 mm, 3 μm TFA (1.5 mL) minutes and holding at 20%for 14B: 1.2 column temp.: 50° C. B: CH₃CN (4L) + 0.5 minutes to 90% Ain 0.01 14F: 1.0 TFA (0.75 mL) min held for 0.49 min. Runtime: A/B/F: 4min  14C From 95% A to 5% A in 0.9 1.2 minutes and holding at 5% for 0.2minutes, to 95% A in 0.01 min held for 0.49 min. Runtime 2 min  14D From95% A to 5% A in 0.9 minutes and holding at 5% for 0.2 minutes, to 95% Ain 0.01 min held for 0.49 min. Runtime 2 min  14E From 10% B to 80% B in0.9 minutes and holding at 80% for 0.6 minutes, to 10% B in 0.01 minheld for 0.49 min. Runtime 2 min 15 Agilent Poroshell A: 0.1% FA in H₂O2.0 min 98% A, from 98% A to 1   120, EC-C18, B: 0.05% FA in CH₃CN 0% Ain 10 min, hold for 3.4 4.6 × 100 mm-4 μm min. Runtime: 15.4 min columntemp.: 30° C. Agilent 1260 Infinity II  16A HALO 90A C18 A: H₂O + 0.05%TFA From 95% A to 0% A in 1   (2.0 μm, 2.1 × 30 mm) B: CH₃CN + 0.05% TFA2.19 min, held for 0.5 min, to column temp.: 40° C. 95% A in 0.05 min,held for 0.25 min. Runtime: 3 min  16B From 95% A to 50% A in 1   2.79min, to 0% A in 1 min, held for 0.6 min, to 95% A in 0.1 min, held for0.5 min. Runtime: 5 min  16C From 95% A to 40% A in 2.79 min, to 0% A in1 min, 1   held for 0.6 min, to 95% A in 0.1 min, held for 0.5 min.Runtime: 5 min 17 Ascentis Express C18 A: H₂O /0.05% TFA From 95% A to50% A in (2.7 μm, 3.0 × 50 mm) B: CH₃CN/0.05% TFA 2.99 min, to 0% A in1.0 min, 1.5 Column temp.: 45° C. held for 0.6 min, to 95% A in Runtime:5.2 min 0.1 min, held for 0.5 min 18 Kinetex EVO C18100A A: H₂O/5 mMFrom 90% A to 5% A in 1.2 (2.6 μm, 3.0 × 50 mm) NH₄HCO₃ 2.99 min, heldfor 0.6 min, to column temp.: 40° C. B: CH₃CN 90% A in 0.10 min, heldfor 0.30 min. Runtime: 4 min  18B From 90% A to 60% A in 3.19 min, to 5%in 0.8 min, held for 0.9 min, to 90% A in 0.2 min, held for 0.20 min.Runtime: 5.3 min 19 Ascentis Express C18 A: H₂O/0.05% TFA From 95% A to5% A in 1.5 (2.7 μm, 3.0 × 50 mm), B: CH₃CN/0.05% TFA 1.99 min, held for0.7 min, column temp.: 40° C. to 95% A in 0.05 min, held for 0.25 min 19A From 95% A to 0% A in 1.99 min, held for 0.7 min, to 95% A in 0.05min, held for 0.25 min. Runtime 3 min  19B From 95% A to 0% A in 1.09min, held for 0.6 min, to 95% A in 0.05 min, held for 0.1 min. Runtime1.85 min 20 HALO 90A C18 A: H₂O/0.05% TFA From 95% A to 50% A in 1.5(2.0 μm, 3.0 × 30 mm), B: CH₃CN/0.05% TFA 3.09 min, to 5% A in 1.0 min,column temp.: 40° C. held for 0.9 min, to 95% A in 0.1 min, held for 0.2min. Runtime: 5.3 min  20A From 95% A to 0% A in 1.99 min, held for 0.7min, to 95% A in 0.05 min, held for 0.25mi. n Runtime: 3 min  20B From95% A to 0% A in 1.99 min, held for 0.7 min, to 95% A in 0.05 min, heldfor 0.45 min. Runtime 3.2 min  20C From 95% A to 60% A in 3.09 min, to10% A in 1.0 min, held for 0.9 min, to 95% A in 0.1 min, held for 0.2min. Runtime: 5.3 min 21 From 90% A to 5% A in 1.99 min, held for 0.7min, to 90% A in 0.05 min, held for 0.25 min  21A Poroshell HPH-C18 A:6.5 mM From 90% A to 55% A in 1.2 (2.7 μm, 3.0 × 50 mm), NH₄HCO₃ + 2.99min, to 5% in 1 min, held Column temp: 40° C. NH₃H₂O for 0.7 min, to 90%A in 0.2 B: CH₃CN min, held for 0.1 min (Run time 5 min)  21B From 90% Ato 60% A in 2.99 min, to 5% in 1 min, held for 0.7 min, to 90% A in 0.2min, held for 0.1 min. Runtime 5 min 22 Ascentis Express C18 A:Water/0.05% TFA From 90% A to 5% A in 1.5 (2.7 μm,4.6 × 100 mm) B:CH₃CN/0.05% TFA 7.99 min, held for 2.0 min, to Column temp: 40° C. 90% Ain 0.5 min, held for 1.5 min. Runtime: 12 min 23 HALO C18 From 95% A to0% A in 1.5 (2.7 μm, 3.0 × 50 mm) 1.99 min, held for 0.7 min, to Columntemp: 40° C. 95% A in 0.05 min, held for 0.25 min. Runtime: 3 min 24HPH-C18 A: 6.5 mM From 90% A to 50% A in 1.2 (2.7 μm, 3.0*50 mm)NH₄HCO₃ + 2.99 min, to 5% A in 0.3 min Column temp: 35° C. NH₃H₂O heldfor 0.45 min, to 90% A in B: CH₃CN 0.05 min, held for 0.2 min. Runtime 4min

2. LCMS Results

The results of LCMS characterizations and the particular set ofconditions used for the compounds disclosed here are presented in Table2.

TABLE 2 Cmp'd [M + H]⁺or LCMS No. Rt (min) [M − H]⁻ method  1 1.660 [M −H]⁻ = 454  2  2 1.035 [M − H]⁻ = 414  3  3 1.394 [M + H]⁺ = 414  4  41.217 [M − H]⁻ = 470  4  5 1.461 [M − H]⁻ = 480  4  6 1.428 [M − H]⁻ =516  4  7 1.429 [M − H]⁻ = 488  4  8 1.375 [M + H]⁺ = 454  5  9 0.734[M + H]⁺ = 453  3  10 1.392 [M + H]⁺ = 425  6  11 1.379 [M + H]⁺ = 434 1  12 1.304 [M + H]⁺ = 449  8  13 0.808 [M + H]⁺ = 468  4  14 1.310[M + H]⁺ = 439  1  15 1.489 [M + H]⁺ = 453  1  16 1.363 [M + H]⁺ = 424 8  17 1.131 [M − H]⁻ = 437  4  18 1.592 [M + H]⁺ = 457  1  19 1.572[M + H]⁺ = 457  1  20 2.692 [M + H]⁺ = 499 13  21 1.331 [M + H]⁺ = 485 1  22 1.536 [M + H]⁺ = 573  1  23 1.504 [M + H]⁺ = 438  1  24 2.246[M + H]⁺ = 453 11  25 1.141 [M + H]⁺ = 440  9  26 1.234 [M + H]⁺ = 46710  27 1.004 [M + H]⁺ = 490  9  28 1.133 [M + H]⁺ = 460 12  29 1.293[M + H]⁺ = 454  9  30 0.950 [M + H]⁺ = 439  9  31 1.862 [M + H]⁺ = 41514A  32 10.91 [M + H]⁺ = 443 15  33 1.427 [M + H]⁺ = 470  9  34 1.036[M + H]⁺ = 502  4  35 1.237 [M + H]⁺ = 439  1  36 1.107 [M + H]⁺ = 42316A  37 1.099 [M + H]⁺ = 405 16A  38 1.075 [M + Na]⁺ = 385  9  39-A2.295 [M + H]⁺ = 439 16B  39-B 2.298 [M + H]⁺ = 439 16B  40-A 2.614 [M +H]⁺ = 447 16B  40 1.229 [M + H]⁺ = 459  9  41 1.441 [M + H]⁺ = 446 16A 42 1.323 [M + H]⁺ = 451  9  43 0.865 [M + H]⁺ = 416  4  44 1.193 [M +H]⁺ = 471 16A  45 1.348 [M − H]⁻ = 508 12  46 1.348 [M − H]⁻ = 502  4 47 1.199 [M − H]⁻ = 412  4  48 1.361 [M − H]⁻ = 454  4  49 1.394 [M −H]⁻ = 468  4  50 1.324 [M − H]⁻ = 466  4  51 1.182 [M − H]⁻ = 456  4  522.541 [M + H]⁺ = 458 16C  53 1.338 [M + H]⁺ = 448  9  54 0.992 [M + H]⁺= 390 14C  55 1.144 [M + H]⁺ = 405 14C  56 2.557 [M + H]⁺ = 391 14B  5710.149 [M + H]⁺ = 415 15  58 1.576 [M + H]⁺ = 465 18  59 0.796 [M + H]⁺= 467  4  60 1.020 [M + H]⁺ = 441  1  60-A 0.933 [M + H]⁺ = 423  4  611.191 [M + Na]⁺ = 523  9  62 1.042 [M + H]⁺ = 453  1  63 1.013 [M + H]⁺= 459  4  63-A 2.290 [M + H]⁺ = 459 11  64 1.410 [M + H]⁺ = 491  1  652.657 [M + Na]⁺ = 495 17  66 1.195 [M + H]⁺ = 416 14C  67 1.525 [M + H]⁺= 509 19  67-A 1.105 [M + H]⁺ = 509 21  68 1.452 [M + H]⁺ = 493 19  68-A1.340 [M + H]⁺ = 493 19  69 1.084 [M + H]⁺ = 477 21  69-A 0.988 [M + H]⁺= 477 21  70 1.428 [M + H]⁺ = 473 19  70-A 1.313 [M + H]⁺ = 473 19  711.518 [M + H]⁺ = 487 19  71-A 1.392 [M + H]⁺ = 487 19  72 1.286 [M + H]⁺= 513 21  72-A 2.349 [M + H]⁺ = 513 21  73 1.393 [M + H]⁺ = 439  1  740.849 [M + H]⁺ = 460 14D  75 2.167 [M + H]⁺ = 449 14B  75A 0.928 [M +H]⁺ = 459 14D  76 1.209 [M + H]⁺ = 495 19  77 2.348 [M + H]⁺ = 481 17 78 1.238 [M + H]⁺ = 427  9  79 0.977 [M + H]⁺ = 417 21  80 1.019 [M +H]⁺ = 469 21  81 1.017 [M + H]⁺ = 513 21  82 1.223 [M + H]⁺ = 448 19  831.079 [M + H]⁺ = 474 21  84 2.612 [M + H]⁺ = 476 17  85 2.864 [M + H]⁺ =488 20  86 1.270 [M + H]⁺ = 451 19  86-A 1.268 [M + H]⁺ = 451 19  86-B1.219 [M + H]⁺ = 451 19  87-A 1.462 [M + H]⁺ = 543 20  87-B 1.453 [M +H]⁺ = 543 20  88-A 0.910 [M + H]⁺ = 453 20  89 2.872 [M + H]⁺ = 465 13 90 9.502 [M + H]⁺ = 442 15  91 11.305 [M + H]⁺ = 498 15  92 10.622 [M +H]⁺ = 494 15  93 2.276 [M + H]⁺ = 463 21A  94 10.309 [M + H]⁺ = 477 15 95 1.231 [M + H]⁺ = 449 12A  96 9.653 [M + H]⁺ = 463 15  97 1.352 [M +H]⁺ = 501 19  98 10.265 [M + H]⁺ = 513 15  99 1.195 [M + H]⁺ = 513 21100 1.188 [M + H]⁺ = 513 21 101 1.448 [M + H]⁺ = 463 19 102 0.973 [M +H]⁺ = 467 20B 103 2.502 [M + H]⁺ = 467 20C 104 1.647 [M + H]⁺ = 462 24105 1.712 [M + H]⁺ = 462 24 106 1.416 [M + H]⁺ = 473 19A 107 9.809 [M +H]⁺ = 499 15 108 0.842 [M + H]⁺ = 511 21 109 0.727 [M + H]⁺ = 511 21 1100.86 [M + H]⁺ = 511 21 111 0.751 [M + H]⁺ = 511 21 112 1.341 [M + H]⁺ =487  5A 113 1.34 [M + H]⁺ = 487 19A 114 1.146 [M + H]⁺ = 515  5B 1151.023 [M + H]⁺ = 515 21 116 2.964 [M + H]⁺ = 507 13B 117 2.709 [M + H]⁺= 507  5C 118 2.733 [M + H]⁺ = 525 13 119 1.257 [M + H]⁺ = 525 19A 1202.733 [M + H]⁺ = 525 13 121 1.257 [M + H]⁺ = 525 19A 122 1.208 [M + H]⁺= 499 19 123 1.098 [M + H]⁺ = 499 19 124 0.94 [M + H]⁺ = 499 21 1251.941 [M + H]⁺ = 499 18B 126 2.381 [M + H]⁺ = 499 22 127 0.731 [M + H]⁺= 499 21 128 0.941 [M + H]⁺ = 510 21 129 0.844 [M + H]⁺ = 510 21 1302.283 [M + H]⁺ = 499 21B 131 1.842 [M + H]⁺ = 499 21B 132 1.003 [M + H]⁺= 510 21 133 0.906 [M + H]⁺ = 510 21 134 1.196 [M + H]⁺ = 510 19A 13510.362 [M + H]⁺ = 500 15 136 9.674 [M + H]⁺ = 500 15 137 7.539 [M + H]⁺= 459 15 138 7.52 [M + H]⁺ = 459 15 139 10.135 [M + H]⁺ = 458 15 1409.48 [M + H]⁺ = 458 15 141 6.874 [M + H]⁺ = 459 15 142 6.669 [M + H]⁺ =459 15 143 8.458 [M + H]⁺ = 446 15 144 1.124 [M + H]⁺ = 469 21 145 9.305[M + H]⁺ = 472 15 146 0.831 [M + H]⁺ = 474 14D 147 0.870 [M + H]⁺ = 47414A 148 9.338 [M + H]⁺ = 414 15 149 8.28 [M + H]⁺ = 421 15 150 8.915[M + H]⁺ = 432 15 151 8.195 [M + H]⁺ = 404 15 152 8.695 [M + H]⁺ = 38915 153 9.801 [M + H]⁺ = 428 15 154 1.963 [M + H]⁺ = 456 14A 155 9.865[M + H]⁺ = 499 15 156 1.418 [M + H]⁺ = 499 19A 157 0.740 [M + H]⁺ = 40514D 158 1.239 [M + H]⁺ = 485 23 159 1.533 [M + H]⁺ = 466 19A 160 0.696[M + H]⁺ = 491 21 161 0.705 [M + H]⁺ = 490 20A 162 0.681 [M + H]⁺ = 40414E 163 1.125 [M + H]⁺ = 487 21 164 1.122 [M + H]⁺ = 487 21 165 0.945[M + H]⁺ = 485 19B 166 1.373 [M + H]⁺ = 485 19A 167 2.345 [M + H]⁺ = 46521A 168 1.092 [M + H]⁺ = 465 21 169 1.041 [M + H]⁺ = 453 21 170 1.046[M + H]⁺ = 453 21 171 1.036 [M + H]⁺ = 390 14F

Example 99: Biological Assays

THR Biochemical Assay

The TR-FRET thyroid receptor beta coactivator assay was used withslight, optimized modifications of the manufacturer's protocol(Invitrogen). The assay uses a terbium-labeled anti-GST antibody, aglutathione-S-transferase (GST) tagged human thyroid receptor, beta oralpha, ligand-binding domain (LBD), and a fluorescein labeled SRC2-2coactivator peptide. The antibody interacts with the LBD, where theagonist also binds, resulting in increased affinity for the SRC2-2coactivator peptide causing energy transfer of the acceptor fluorophoreand a FRET emission shift from 495 to 520 nm. The energy transfer isdetected as an increase in the fluorescence emission of the fluoresceinacceptor, and a decrease in the fluorescence emission of the terbiumdonor. The assay is performed in a 384-well black plate in a finalvolume of 20 μL. Serial dilution of various test agonists was performedin DMSO (1% final DMSO concentration) and added to the test plate.Thyroid receptor beta LBD is added to the plate at a final concentrationof 1 nM, followed by the mixture of the fluorescein labeled SRC2-2coactivator peptide, and the terbium-labeled anti-GST antibody at finalconcentrations of 200 nM and 2 nM respectively. The assay is incubatedfor 1 hr at rt protected from light. The TR-FRET is then measured on aVictor multilabel reader (Perkin Elmer) using an excitation wavelengthof 340 nm with emission filters of 495 nm and 520 nm. The assay isquantified by expressing a ratio (520:495) of the intensities, and theresulting activation curves; EC₅₀ values were generated using asigmoidal dose response (variable slope) equation in GraphPad™ Prism8.0.

HEK293T reporter THRalpha/beta/RXR reporter assay (assay 2)

The purpose of this assay is to evaluate the effect of compounds on thethyroid hormone nuclear receptor pathway in HEK293T cells. To this end,HEK293T cells are transiently transfected with a luciferase reporterunder the control of the thyroid response element (TRE), an RXRexpression plasmid and either a THR alpha or THR beta expressionplasmid. Transfected cells are stimulated with test compounds for 18-24hours before activation of the thyroid hormone pathway is measured via aluciferase read-out.

Procedure. 24 hours prior to transfection, approximately 7×10⁵ HEK293 T(ATCC, catalog #CRL-3216) are plated in one well of a 6-well-plate usingDMEM (Hyclone, catalog #SH30022) supplemented with 10% FBS (Gibco,catalog #16000-044) and incubated overnight. Transfection complexes areprepared by mixing 12 μL of Lipofectamine 2000 (Invitrogen catalog#11668019) with 4 μg of a plasmid mixture at a ratio of 1:1:4 (TRalphaor TRbeta: RXR: TRE-Luc) in 200 μL OptiMem (Invitrogen catalog#11058-021) and added to the cells. After overnight incubation,transfected cells are re-seeded at (1×10⁴ cells/well, 30 L/well) in a384 microplate and incubated for an additional 5-6 hours. Ten five-folddilutions of test compounds are prepared in DMSO and 30 nL are dispensedto the cells. Pure DMSO serves as negative control while T3 (MCE catalog#HY-A0070) and GC-1 (MCE catalog #HY-14823) are used as positivecontrols. Approximately 18-24 h after compound addition, 384 well platesare allowed to adjust to rt, 30 μL One-Glo (Promega catalog #E6120) isadded to each well and luminescence is measured on a Perkin ElmerEnspire plate reader. Percent agonism is calculated using the followingequation: 100× (sample-negative control)/(positive control-negativecontrol).

Huh-7 Differential Gene Expression (Assay 3)

Serum Stripping

AG® 1-X8 Anion Exchange Resin (analytical grade, 200-400 mesh, chlorideform; 1401451, Bio-Rad) was pre-washed with distilled water three times;water was separated from resin via centrifugation. Fetal bovine serum(FBS) was incubated with washed resin (50 mg resin/mL FBS; resin weightis dry weight of resin prior to washing) for 5 hr at room temperature ona rotor. The FBS was separated from the resin via centrifugation andincubated with new, washed resin for 18 h at room temperature on arotor. The resin-treated FBS (rFBS) was separated via centrifugation andthen sterilized via filtration (0.22 μM PES membrane).

Cell Culture and Drug Treatment

Huh-7 cells were cultured in DMEM (10-013-CM, Corning) supplemented with10% FBS and 1% Pen-Strep at 37° C. under 5% C₀₂. When 70-80% confluencewas reached, the cells were removed by trypsinization. The medium wasaspirated from the cell culture dish, the cell monolayer was washed with1×PBS, and 0.05% trypsin, 0.53 mM EDTA (25-052-CV, Corning) solution wasadded to the dish. After 3 min incubation, the cells were detachedcompletely by repeatedly pipetting solution onto the monolayer. Equalvolume of DMEM supplemented with 10% rFBS and 1% Pen-Strep (TH-depletedDMEM) was added to the dish to inactivate the trypsin. The cellsuspension was centrifuged at 350×g at room temperature for 3 min. Thesupernatant was aspirated out and the cell pellet was resuspended inTH-depleted DMEM. Cell density was quantified with a Vi-CELL XR CellViability Analyzer (Beckman Coulter) and cells were seeded onto CollagenI 96-well plates (356407, Corning) at 50,000 cells/well in 150 μLTH-depleted DMEM; the outer, perimeter wells were not used to avoid edgeeffect. After 24 hr incubation, the media was replaced with treatmentmedia. All compounds were serially diluted in DMSO and finalconcentrations were reached by dilution in TH-depleted DMEM (0.1% DMSO).The cells were incubated in treatment media for 24 hr. Treatments wereperformed in biological duplicates.

Cell Lysis and RT-qPCR

After 24 hr in treatment media, the cells were lysed directly on theculture plates and cDNA was produced using the TaqMan™ Fast AdvancedCells-to-CT™ Kit (A35374, Invitrogen) and following the manufacturer'sprotocol. RT-qPCR for CPT1A (Hs00912671_m1) and two housekeeping genes,ACTB (Hs01060665_g1) and TFG (Hs02832013_g1), was performed usingTaqMan™ Fast Advanced Master Mix. RT-qPCR reactions were run on theqTOWER³ 84 G (Analytik Jena) in technical duplicates.

Data Analysis

ΔRn values were obtained from the qPCRsoft384 1.0 software and CPT1Agene expression was quantified via the 2-ΔΔCt method. Dose-responsecurves were generated using GraphPad Prism 8 using four parameterlogistic equation without top constraint to derive EC₅₀ and E_(max).

Compounds of Formula (I) are active as THR-beta agonists as shown inTable 3, where: for Assay 1: ‘A’ indicates an EC₅₀<50 nM, ‘B’ indicatesan EC₅₀ of ≥50 nM and 250 nM, ‘C’ indicates an EC₅₀≥250 nM and <1000 nM,‘D’ indicates an EC₅₀≥1000 nM and <25000 nM, and ‘E’ indicates anEC₅₀>25000 nM. For Assay 2, ‘A’ indicates an EC₅₀<50 nM, ‘B’ indicatesan EC₅₀ of ≥50 nM and <250 nM, ‘C’ indicates an EC₅₀≥250 nM and <1000nM, ‘D’ indicates an EC₅₀≥1000 nM and <10000 nM, and ‘E’ indicates anEC₅₀>10000 nM.

TABLE 3 Compound Activity category number Assay 1 Assay 2  1 A B  2 A B 3 A B  4 A D  5 A C  6 E  7 E  8 E  9 D  10 B B  11 A B  12 C D  13 E E 14 E  15 E E  16 B B  17 A D  18 A D  19 A D  20 E E  21 B E  22 E  23D  24 E  25 D  26 E  27 E  28 B C  29 C C  30 E  31 A C  32 A B  33 C 34 D  35 D D   35-A B E  36 A A  37 B B  38 C C   39-A A B   39-B A A  40-A C D  40 A B  41 A A  42 A B  43 A  44 B E  45 A B  46 A D  47 A D 48 A B  49 A C  50 A B  51 D E  52 B E  53 A C  54 A A  55 A A  56 A B 57 A B  58 A B  59 D D  60 C D   60-A A C  61 A B   61-A A A   61-B B C 62 D E  63 B B   63-A E E  64 A B  65 A B  66 B D  67 B B   67-A A  68A A   68-A E  69 B B   69-A E  70 A A   70-A E  71 A A   71-A E  72 B B  72-A A B  73 B B  74 D E  75 A A   75A A  76 D C  77 B B  78 C  79 D E 80 A A  81 A A  82 A A  83 A A  84 A B  85 A   86-A B B   86-B B C  87-A C E   87-B E   88-A D E  89 A  90 A E  91 A B   91-A A B  92 B B  92-A A C  93 B C  94 B B  95 B B  96 A A  97 C D  98 B B  99 B E 100 BB 101 B B 102 D D 103 D D 104 C D 105 D 106 C D 107 A B 108 E 109 E 110E 111 E 112 B B 113 B C 114 B C 115 B C 116 B B 117 B E 118 A A 119 D E120 A B 121 B B 122 D 123 E 124 D E 125 D 126 E 127 E 128 E E 129 C E130 E 131 D 132 E 133 C 134 A C 135 E 136 D 137 D 138 E 139 B A 140 E141 D 142 E 143 A A 144 B C 145 A D 146 A A 147 A A 148 A D 149 A A 150A A 151 A A 152 A A 153 A 154 B E 155 B C 156 A B 157 A A 158 A B 159 BB 160 D E 161 C D 162 A 163 E 164 A 165 A 166 B 167 B 168 A 169 A 170 B

Compounds of Formula (I) may have activity as TER-alpha agonists asshown in Table 4, where: for Assay 1: ‘A’ indicates an EC₅₀<50 nM, 6B′indicates an EC₅₀ of ≥50 nM and <250 nM, ‘C’ indicates an EC₅₀≥250 nMand <1000 nM, ‘D’ indicates an EC₅₀≥1000 nM and <25000 nM, and ‘E’indicates an EC₅₀≥25000 nM. For Assay 2, ‘A’ indicates an EC₅₀<50 nM,‘B’ indicates an EC₅₀ of ≥50 nM and <250 nM, ‘C’ indicates an EC₅₀≥250nM and <1000 nM, ‘D’ indicates an EC₅₀≥1000 nM and <10000 nM, and ‘E’indicates an EC₅₀>10000 nM.

TABLE 4 Compound Activity category number Assay 1 Assay 2  1 A C  2 A C 3 E C  4 E E  5 E D  6 E  7 E  8 D  9 E  10 C B  11 B C  12 D D  13 C D 14 E  15 E E  16 C C  17 E E  18 E D  19 E D  20 E E  21 E E  22 E  23D  24 E  25 D  26 E  27 E  28 C D  29 D C  30 E  31 A D  32 A B  33 C 34 E  35 D D   35-A C B  36 B A  37 C B  38 D E   39-A C B   39-B B A  40-A C D  40 B C  41 A A  42 C C  43 A A  44 E E  45 A C  46 E E  47 AD  48 A C  49 A C  50 A C  51 E E  52 D E  53 C D  54 A A  55 A B  56 CB  57 A C  58 C C  59 D E  60 D D   60-A B C  61 C C   61-A B B   61-B DC  62 D E  63 C C   63-A E E  64 C C  65 C D  66 C D  67 D E   67-A E D 68 B B   68-A E  69 C B   69-A E  70 B B   70-A E  71 B B   71-A E  72E E   72-A B E  73 C C  74 D E  75 B C   75-A B E  76 E E  77 C C  78 D 79 D D  80 B B  81 A A  82 A A  83 A A  84 A B  85 A A   86-A C C  86-B D D   87-A C E   87-B E   88-A E E  89 C D  90 B E  91 D E   91-AD E  92 D E   92-A D E  93 C D  94 C D  95 C C  96 B B  97 D E  98 E E 99 E E 100 E E 101 C B 102 D E 103 E E 104 D E 105 D 106 D D 107 D C108 E 109 E 110 E 111 E 112 C D 113 C E 114 E E 115 E E 116 E E 117 E E118 B B 119 E E 120 E E 121 C E 122 D 123 E 124 D E 125 E 126 E 127 E128 E E 129 E E 130 D 131 D 132 E 133 E 134 C E 135 E 136 D 137 E 138 E139 B B 140 E 141 E 142 E 143 A A 144 C D 145 A D 146 B B 147 A A 148 AD 149 A A 150 A A 151 A A 152 A A 153 A 154 E 155 E E 156 B D 157 C B158 C D 159 C D 160 D E 161 C E 162 B 163 E 164 B C 165 C 166 E 167 D168 B 169 C 170 E

Compounds of Formula (I) have activity as THR-alpha/beta agonists asshown in Table 5, where: for Assays 1 and 2: ‘C’ indicates anE_(max)<50%, ‘B’ indicates an E_(max)≥50%, and <75%, ‘A’ indicates anE_(max)≥75%.

TABLE 5 Activity category Compound Assay 1 Assay 2 number THRα THRβ THRαTHRβ  1 C B A A  2 C A A A  3 C B A A  4 C C B A  5 C C B A  6 C C  7 CC  8 C C  9 C C  10 B B A A  11 C C A A  12 B A A A  13 C C A A  14 C C 15 C C C C  16 C B A A  17 C C C A  18 C C B A  19 C C C A  20 C C C C 21 C C C C  22 C C  23 C C  24 C C  25 B B  26 C C  27 C C  28 B C B A 29 B B A A  30 A B  31 C B A A  32 B A A A  33 C A  34 C C  35 B B C B 35-A B C C A  36 B B C B  37 B B B A  38 A B C A  39-A B C A A  39-B BB A A  40-A C C C A  40 B B A A  41 B B B A  42 C B A A  43 A A A A  44C C C C  45 C C A A  46 C C C B  47 C C A A  48 B B A A  49 C C C A  50B B A A  51 A C C C  52 C C B A  53 C B A A  54 C B B A  55 B B A A  56C C B A  57 C C A A  58 C C B A  59 C C B A  60 C C A A  60-A C C C B 61 B C A A  61-A B B B A  61-B C C C A  62 C C B A  63 C C B A  63-A CC C C  64 C C C B  65 C C C A  66 C B B A  67 C C C B  67-A C C C C  68C B B A  68-A C C  69 C C B B  69-A C C  70 C C B A  70-A C C  71 C C BA  71-A C C  72 C C C B  72-A C C C B  73 B C A A  74 C B C C  75 A A AA  75-A C B C B  76 C C C B  77 B C A A  78 C C  79 C B B A  80 B B A A 81 B B A A  82 A A A A  83 B B A B  84 B C A A  85 C C B A  86-A C C BA  86-B C C C A  87-A C C C C  87-B C C  88-A C C A C  89 C C C B  90 CC C B  91 B C C B  91-A C C C B  92 C C C C  92-A B C C C  93 C C C B 94 C C C B  95 C C C A  96 C C B A  97 C C C C  98 C C C C  99 A C C C100 C C C C 101 C C C B 102 C C C C 103 C C C C 104 B C C B 105 C C 106C C C B 107 C C C B 108 C C 109 C C 110 C C 111 C C 112 C C C C 113 C CC C 114 C C C C 115 C C C C 116 C C C C 117 C C C C 118 C B B B 119 C CC C 120 C C C B 121 C C C B 122 C C 123 C C 124 C C C C 125 C C 126 C C127 C C 128 C C C C 129 C C C C 130 C C 131 C C 132 C C 133 C C 134 C CC B 135 C C 136 C C 137 C C 138 C C 139 C C C B 140 C C 141 C C 142 C C143 A B A A 144 C C B B 145 B C B B 146 C C C B 147 C B A A 148 B C C B149 C C A A 150 C C B B 151 A B B B 152 B C B B 153 C C 154 C C C 155 CC C C 156 C C C B 157 B A B A 158 C C C B 159 C C C B 160 C C C C 161 CC C C 162 C B 163 C C 164 C C B A 165 C C 166 C C 167 C C 168 B C 169 CC 170 C C

Compounds of Formula (I) have activity as THR agonists as shown in Table6, where: for Assay 3 in the EC₅₀ column: ‘A’ indicates an EC₅₀<100 nM,‘B’ indicates an EC₅₀ of ≥100 nM and <1000 nM, ‘C’ indicates an EC₅₀≥100nM. In the E_(max) column, ‘C’ indicates an E_(max)<50%, ‘B’ indicatesan E_(max)≥50%, and <75%, ‘A’ indicates an E_(max)≥75%.

TABLE 6 Activity category Compound Assay 3 Reference EC₅₀ E_(max) (T3) AA  1 B A  10 A B  11 A A  13 C A  16 B C  18 C A  31 B A   39-A A B  39-B A A  40 A A  42 A B  43 A A  52 C A  54 A A  55 A A   61-A A B  61-B C A  67 C A   67-A B C  70 A B  72 B A   72-A B A   75-A C A  83A A   86-A A B  89 B A  90 C B  93 A B  94 B B 101 A C 112 B A 114 B B115 C A 120 B A 121 B B 145 B A 146 B A 148 B A 151 A A 157 A A 158 C C164 A B

Example 100: X-Ray Diffraction Data

The chemical structures of compounds 67 and 67-A were confirmed by x-raycrystallography as described below.

Experimental. Single colorless chunk crystals of compound 67recrystallized from a mixture of THF and acetonitrile by slowevaporation. A suitable crystal with dimensions 0.39×0.20×0.10 mm3 wasselected and mounted on a nylon loop with paratone oil on a BrukerAPEX-II CCD diffractometer. The crystal was kept at a steady T=173(2) Kduring data collection. The structure was solved with the XT (Sheldrick,2015) solution program using dual methods and by using OLEX2 as thegraphical interface. The model was refined with ShelXL 2018/3(Sheldrick, 2015) using full matrix least squares minimization on F2.

Crystal Data. C₂₉H₂₅Cl₂N₇O₅, Mr=622.46, triclinic, P-1 (No. 2),a=8.91530(10) Å, b=10.93240(10) Å, c=16.2174(2) Å, α=75.7870(10°),β=83.5020(10°), γ=67.6090(10°), V=1416.39(3) Å³, T=173(2) K, Z=2, Z′=1,μ(CuK_(α))=2.518, 22070 reflections measured, 5231 unique (Rint=0.0434)which were used in all calculations. The final wR2 was 0.1228 (all data)and R1 was 0.0445 (I>2(I)).

Experimental. Single colorless block crystals of compound 67-Arecrystallized from THF by slow evaporation. A suitable crystal withdimensions 0.14×0.07×0.04 mm3 was selected and mounted on a nylon loopwith paratone oil on a Bruker APEX-II CCD diffractometer. The crystalwas kept at a steady T=173(1) K during data collection. The structurewas solved with the ShelXT (Sheldrick, G. M. (2015). Acta Cryst. A71,3-8) solution program using dual methods and by using OLEX2 as thegraphical interface. The model was refined with ShelXL (Sheldrick, ActaCryst. A64 2008, 112-122) using full matrix least squares minimizationon F2.

Crystal Data. C₂₇H₂₂Cl₂N₆O₅, Mr=581.40, monoclinic, C₂/c (No. 15),a=38.956(17) Å, b=8.001(3) Å, c=23.093(13) Å, R=125.580(12°), α=γ=90°,V=5854(5) Å³, T=173(1) K, Z=8, Z′=1, μ(CuK_(α))=2.389, 44732 reflectionsmeasured, 5360 unique (Rint=0.1596) which were used in all calculations.The final wR2 was 0.3362 (all data) and R1 was 0.1018 (I>2(I)).

Example 101: Comparison of Compounds 42, 40, and 10 with —CNCounterparts

Compounds 42, 40, and 10 have R₉═NH₂. These compounds were compared todirect analogs wherein R₉═CN, in the HEK293T reporter THRalpha/beta/RXRreporter assay.

TABLE 7 HEK293T reporter THRalpha/beta/RXR reporter assay data Compd 42CN analog 1 Compd 40 CN analog 2 Compd 10 CN analog 3 EC₅₀ α (μM)0.834 >10 0.564 9.65 0.191 16.9  (87%) (95%) (35%) (79%) (62%) EC₅₀ β(μM) 0.077 >10 0.058 3.78 0.050  2.37 (94%) (92%) (81%) (91%) (93%)Ratio (α/β) 11 (n = 5) — 10 (n = 3) 2.5 (n = 1) 4 (n = 7) >4 (n = 4)

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Embodiment 1. A compound of Formula I:

TL-L_(a)-CE-HD  (I)

or a pharmaceutically acceptable salt, prodrug, amide or ester thereof,wherein:

i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

wherein:

each of Q₁, Q₂, Q₃, Q₄, Qs, Q₆, and Qs, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is hydrogen, an optionally substituted alkyl, an optionallysubstituted carbocyclic group, an optionally substituted aryl group, anoptionally substituted heterocyclic group, an optionally substitutedheteroaryl group, an optionally substituted carbocyclic alkyl group, anoptionally substituted aralkyl group, an optionally substitutedheterocyclicalkyl group, an optionally substituted heteroarylalkylgroup, an optionally substituted amino group, an optionally substitutedC-carboxy or O-carboxy group, —CN, an optionally substituted carbamoylgroup, or an optionally substituted carbamoyl alkyl group, where thenitrogen of the carbamoyl or carbamoyl alkyl group is optionally aheteroatom in a ring structure;

R₂ is hydrogen, halogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, or —CN;

R₃ is hydrogen or lower alkyl;

R₄ is an optionally substituted alkyl, an optionally substitutedcarbocyclic group, an optionally substituted aryl group, an optionallysubstituted heterocyclic group, an optionally substituted heteroarylgroup, an optionally substituted carbocyclic alkyl group, an optionallysubstituted aralkyl group, an optionally substituted heterocyclicalkylgroup, an optionally substituted heteroarylalkyl group, an optionallysubstituted amino group, an optionally substituted sulfamoyl group, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutedcarbocyclic group, optionally substituted aryl group, optionallysubstituted heterocyclic group, or optionally substituted heteroarylgroup;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

or when Q₆ is nitrogen and R₅ is hydroxy, then the tautomer of themoiety of Formula III; and

Alk is hydrogen or an optionally substituted alkyl;

ii) CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

optionally R₇ and R₈ taken together, along with the carbon atoms towhich they are attached, form a 4, 5- or 6-membered carbocyclic,heterocyclic, aryl, or heteroaryl ring

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

iii) HD is a moiety of Formula V or VI:

wherein:

-   -   R₉ is selected from hydrogen, —(C(R_(d))₂)_(n)—C(R_(a))₃,        —(C(R_(d))₂)_(n)—OR_(d), —(C(R_(a))₂)_(n)—N(R_(a))₂,        —(C(R_(a))₂)_(n)—S(═O)_(q)R_(d), —(C(R_(a))₂)_(n)—CN,        —(C(R_(a))₂)_(n)—C≡C—R_(d), —(C(R_(d))₂)_(n)—C(═O)—OR_(d),        —(C(R_(a))₂)_(n)—HeAr, or —(C(R_(a))₂)_(n)—C(═O)—N(R_(a))₂;        wherein

each R_(d) is independently hydrogen or optionally substituted loweralkyl;

each q is independently selected from 0, 1, or 2; and

each n is independently selected from 0, 1, 2, 3, 4, or 5;

R₁₀ is hydrogen, —C(R_(e))₃, wherein each R_(e) is independentlyhydrogen, halogen, or optionally substituted lower alkyl; and

R₁₁ is an aryl group, preferably substituted with lower alkyl, halogen,cycloalkyl; or a bicyclic ring system containing either aromatic orsaturated rings; or a bicyclic heterocyclic containing either aromaticor saturated ring systems

iv) L_(a) is independently a bond; —(C(R_(a))₂)_(n)—; oxygen; sulfur;—NR_(a)—; wherein:

each R_(a) is independently a hydrogen or lower alkyl; and

n is 0, 1, 2, 3, 4 or 5.

Embodiment 2. The compound of Embodiment 1, wherein R₁ is hydrogen, anoptionally substituted alkyl, an optionally substituted carbocyclicgroup, an optionally substituted aryl group, and an optionallysubstituted C-carboxy group.

Embodiment 3. The compound of Embodiment 2, wherein the alkyl isselected from the group consisting of methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, and t-butyl.

Embodiment 4. The compound of Embodiment 3, wherein at least one carbonatom of the listed alkyl moieties is perfluorinated.

Embodiment 5. The compound of Embodiment 3, wherein the alkyl issubstituted with cycloalkyl or aryl.

Embodiment 6. The compound of Embodiment 5, wherein the cycloalkyl isselected from the group consisting of cyclopropyl, cyclopentyl, andcyclohexyl.

Embodiment 7. The compound of Embodiment 5, wherein the aryl isoptionally substituted phenyl.

Embodiment 8. The compound of Embodiment 2, wherein the carbocyclicgroup is cyclohexane or cyclopentane.

Embodiment 9. The compound of Embodiment 2, wherein the aryl group isphenyl.

Embodiment 10. The compound of Embodiment 2, wherein the C-carboxy groupis a moiety of formula —C(═O)—O—R, where R is selected from the groupconsisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, andt-butyl.

Embodiment 11. The compound of Embodiment 1, wherein R₂ is selected fromthe group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, and t-butyl.

Embodiment 12. The compound of Embodiment 1, wherein Q₁, Q₂, Q₃, and Q₄are —CR_(b)—, where each R_(b) is independently selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl.

Embodiment 13. The compound of Embodiment 1, wherein each of Q₅ and Q₆is independently nitrogen or —NH.

Embodiment 14. The compound of Embodiment 13, wherein Q₅ is nitrogen andQ₆ is —NH.

Embodiment 15. The compound of Embodiment 1, wherein R₄ is selected fromthe group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, and t-butyl.

Embodiment 16. The compound of Embodiment 1, wherein R₅ is hydroxy.

Embodiment 17. The compound of Embodiment 1, wherein each of R₆ and R₇is independently chlorine, bromine, and iodine.

Embodiment 18. The compound of Embodiment 17, wherein each of R₆ and R₇is independently —CN, an optionally substituted lower alkyl or anoptionally substituted lower alkoxy, where the lower alkyl and the alkylgroup of the lower alkoxy is each independently selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl.

Embodiment 19. The compound of Embodiment 1, wherein R₆ and R₇ are thesame.

Embodiment 20. The compound of Embodiment 1, wherein each of R₆ and R₇is independently chlorine or methyl.

Embodiment 21. The compound of Embodiment 1, wherein R₈ is hydrogen.

Embodiment 22. The compound of Embodiment 1, wherein R_(e) is hydrogenor methyl.

Embodiment 23. The compound of Embodiment 1, wherein:

TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId;

wherein:

each of Q₁, Q₂, Q₃, Q₄, Q₅, Q₆ and Qs, is independently nitrogen or—CR_(b)—, wherein each R_(b) is independently hydrogen, halogen, orlower alkyl;

R₁ is an optionally substituted alkyl, an optionally substitutedcarbocyclic group, an optionally substituted aryl group, an optionallysubstituted heterocyclic group, an optionally substituted heteroarylgroup, an optionally substituted carbocyclic alkyl group, an optionallysubstituted aralkyl group, an optionally substituted heterocyclicalkylgroup, an optionally substituted heteroarylalkyl group, an optionallysubstituted amino group, an optionally substituted C-carboxy orO-carboxy group, —CN, an optionally substituted carbamoyl group, or anoptionally substituted carbamoyl alkyl group, where the nitrogen of thecarbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ringstructure;

R₂ is halogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or —CN;

R₃ is hydrogen;

R₄ is an optionally substituted alkyl, an optionally substitutedcarbocyclic group, an optionally substituted aryl group, an optionallysubstituted heterocyclic group, an optionally substituted heteroarylgroup, an optionally substituted carbocyclic alkyl group, an optionallysubstituted aralkyl group, an optionally substituted heterocyclicalkylgroup, an optionally substituted heteroarylalkyl group, an optionallysubstituted amino group, an optionally substituted sulfamoyl group, anoptionally substituted carbamoyl group, or an optionally substitutedcarbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoylalkyl group is optionally a heteroatom in a ring structure; and

R₅ is hydroxy, NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a five- or six-membered optionally substitutedcarbocyclic group, optionally substituted aryl group, optionallysubstituted heterocyclic group, or optionally substituted heteroarylgroup;

or R₄ and R₅ taken together along with the carbon atoms to which theyare attached form a seven to eleven membered, optionally substitutedspirocyclic ring or a seven to eleven membered, optionally substitutedspiro-heterocyclic ring;

or when Q₆ is nitrogen and R₅ is hydroxy, then the tautomer of themoiety of Formula III; and

Alk is hydrogen or an optionally substituted alkyl;

CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

HD is a moiety of Formula V or VI:

wherein:

R₉ is selected from —NH₂, —CN, —CH₂—S—CH₃, or —CH₂—S(═O)₂—CH₃;

R₁₀ is —CH₃; and

L_(a) is oxygen or —CH₂—.

Embodiment 24. The compound of Embodiment 1, wherein:

TL is a moiety of Formula II

wherein:

each of Q₁, Q₂, and Q₃ is independently nitrogen or —CR_(b)—, whereineach R_(b) is independently hydrogen, halogen, or lower alkyl;

R₁ is an optionally substituted alkyl, an optionally substitutedcarbocyclic group, an optionally substituted aryl group, an optionallysubstituted heterocyclic group, an optionally substituted heteroarylgroup, an optionally substituted carbocyclic alkyl group, an optionallysubstituted aralkyl group, an optionally substituted heterocyclicalkylgroup, an optionally substituted heteroarylalkyl group, an optionallysubstituted amino group, an optionally substituted C-carboxy orO-carboxy group, —CN, an optionally substituted carbamoyl group, or anoptionally substituted carbamoyl alkyl group, where the nitrogen of thecarbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ringstructure;

R₂ is halogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or —CN;

R₃ is hydrogen;

CE is a moiety of Formula IV

wherein:

each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl;

R₈ is selected from hydrogen, optionally substituted lower alkyl,optionally substituted lower alkoxy, cyano, or halogen;

Q₇ is nitrogen or —CR_(c)—, wherein R_(c) is hydrogen, halogen, or loweralkyl;

(TL) denotes the point where the moiety of Formula IV connects toTL-L_(a)-; and

(HD) denotes the point where the moiety of Formula IV connects to -HD;

HD is a moiety of Formula V:

wherein R₉ is hydrogen, —CN, —C(R_(d))₂—S—R_(d), —C(R_(d))₂—S(═O)₂R_(d),or —C≡C—R_(d), wherein each R_(d) is independently hydrogen or loweralkyl; and

L_(a) is oxygen or —CH₂—.

Embodiment 25. A compound selected from the group consisting of:

Embodiment 26. A method of treating a thyroid hormone receptor relateddisorder in a patient, the method comprising the steps of:

identifying a patient in need of treatment for the thyroid hormonereceptor related disorder, and administering to the patient, orcontacting the patient with, a compound of Embodiment 1.

Embodiment 27. The method of Embodiment 26, wherein the thyroid hormonereceptor related disorder is selected from non-alcoholic steatohepatitis(NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liversteatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, andthyroid cancer.

Embodiment 28. A method of selectively modulating the activity of athyroid hormone receptor beta (THR-β) comprising contacting a compoundof Embodiment 1 with a thyroid hormone receptor.

Embodiment 29. The method of Embodiment 28, wherein the contacting is invitro or ex vivo.

Embodiment 30. The method of Embodiment 28, wherein the contacting is invivo.

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds, or compositions, which can ofcourse vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

1.-170. (canceled)
 171. A compound of Formula I′:TL-L_(a)-CE-HD  (I′) or a stereoisomer or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein: i) TL is a moiety ofFormula IIa, IIb, IIIa, IIIb, IIIc, or IIId:

wherein: each of Q₁, Q₂, Q₃, Q₄, Qs, Q₆, and Qs, is independentlynitrogen or —CR_(b)—, wherein each R_(b) is independently hydrogen,halogen, or lower alkyl; R₁ is hydrogen, an optionally substitutedalkyl, an optionally substituted non-aromatic carbocyclic group, anoptionally substituted aryl group, an optionally substitutedheterocycloalkyl group, an optionally substituted heteroaryl group, anoptionally substituted (carbocyclic)alkyl group, an optionallysubstituted aralkyl group, an optionally substituted(heterocycloalkyl)alkyl group, an optionally substituted(heteroaryl)alkyl group, an optionally substituted amino group, anoptionally substituted C-carboxy or O-carboxy group, —CN, an optionallysubstituted carbamoyl group, or an optionally substituted carbamoylalkyl group, where the nitrogen of the carbamoyl or carbamoyl alkylgroup is optionally a heteroatom in a ring structure; R₂ is hydrogen,halogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or —CN; R₃ is hydrogen or lower alkyl; R₄ is an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted non-aromatic carbocyclic group, an optionally substitutedaryl group, an optionally substituted heterocyclic group, an optionallysubstituted heteroaryl group, an optionally substituted(carbocyclic)alkyl group, an optionally substituted aralkyl group, anoptionally substituted (heterocycloalkyl)alkyl group, an optionallysubstituted (heteroaryl)alkyl group, an optionally substituted aminogroup, an optionally substituted sulfamoyl group, an optionallysubstituted carbamoyl group, or an optionally substituted carbamoylalkyl group, where the nitrogen of the carbamoyl or carbamoyl alkylgroup is optionally a heteroatom in a ring structure; and R₅ is hydroxy,NH₂, alkylamino, alkanoylamino, or alkylsulfonylamino; or R₄ and R₅taken together along with the carbon atoms to which they are attachedform a five- or six-membered optionally substituted non-aromaticcarbocyclic group, optionally substituted aryl group, optionallysubstituted heterocyclic group, or optionally substituted heteroarylgroup; or R₄ and R₅ taken together along with the carbon atoms to whichthey are attached form a seven to eleven membered, optionallysubstituted spirocyclic ring or a seven to eleven membered, optionallysubstituted spiro-heterocyclic ring; Alk is hydrogen or an optionallysubstituted alkyl; and R₁₁ is an aryl group optionally substituted withone to five substituents independently selected from lower alkyl,alkoxy, haloalkoxy, halogen, and cycloalkyl; or a heteroaryl groupoptionally substituted with one to five substituents independentlyselected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl;or a bicyclic ring system; or a bicyclic heterocyclic ring system; ii)CE is a moiety of Formula IV

wherein: each of R₆ and R₇ is independently selected from halogen, —CN,optionally substituted lower alkyl, optionally substituted lower alkoxy,optionally substituted lower alkenyl, or cyclopropyl; R₈ is selectedfrom hydrogen, optionally substituted lower alkyl, optionallysubstituted lower alkoxy, cyano, or halogen; optionally R₇ and R₈ takentogether, along with the carbon atoms to which they are attached, form a4-, 5- or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl,or heteroaryl ring Q₇ is nitrogen or —CR_(c)—, wherein R_(c) ishydrogen, halogen, or lower alkyl; (TL) denotes the point where themoiety of Formula IV connects to TL-L_(a)-; and (HD) denotes the pointwhere the moiety of Formula IV connects to -HD; iii) HD is a moiety ofFormula V:

wherein: R₉ is —(C(R_(d))₂)_(n)—N(R_(d))₂, wherein each R_(d) isindependently hydrogen or optionally substituted lower alkyl; and each nis independently selected from 0 or 1; and L_(a) is independently abond; —(C(R_(a))₂)_(z)—; oxygen; sulfur; or —NR_(a)—; wherein each R_(a)is independently a hydrogen or lower alkyl; and z is 0, 1, 2, 3, 4 or 5.172. The compound of claim 171, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein: TL is a moietyof Formula IIIb:


173. The compound of claim 172, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein R₄ is C₁-C₆alkyl; C₂-C₁₀ alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀aryl group; a 3- to 6-membered heterocycloalkyl ring containing one tofour ring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a(heterocycloalkyl)alkyl group; and R₄ is optionally substituted with oneto five R_(g) independently selected from the group consisting ofhydroxy, halogen, CN, C₁-C₆ alkyl, C₆-C₁₀ aryl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, and C₆-C₁₀ aralkoxy, or two R_(g) together with the atoms towhich they are attached form an aromatic or non-aromatic 3- to6-membered ring, optionally containing one or two ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen.
 174. Thecompound of claim 171, or a stereoisomer or a tautomer thereof, or apharmaceutically acceptable salt thereof, wherein: TL is a moiety ofFormula IIIa:


175. The compound of claim 174, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein TL is a moiety ofFormula IIIaa:

wherein each R_(g) is independently C₁-C₆ alkyl or the two R_(g)together with the atom(s) to which they are attached form a 3- to6-membered non-aromatic carbocyclic group.
 176. The compound of claim174, or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein TL is a moiety of Formula IIIab:

wherein R_(g) is C₁-C₆ alkyl.
 177. The compound of claim 174, or astereoisomer or a tautomer thereof, or a pharmaceutically acceptablesalt thereof, wherein TL is a moiety of Formula IIIac:

wherein R_(g) is C₁-C₆ alkyl.
 178. The compound of claim 174, or astereoisomer or a tautomer thereof, or a pharmaceutically acceptablesalt thereof, wherein TL is a moiety of Formula IIIad:

wherein each R_(g) is independently hydrogen or C₁-C₆ alkyl.
 179. Thecompound of claim 174, or a stereoisomer or a tautomer thereof, or apharmaceutically acceptable salt wherein: R₄ is C₁-C₆ alkyl; C₂-C₁₀alkenyl; a non-aromatic C₃-C₁₂ carbocyclic ring, a C₆-C₁₀ aryl group; a3- to 6-membered heterocycloalkyl ring containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen; afive- to ten-membered heteroaryl ring containing one to four ringheteroatoms independently selected from oxygen, sulfur, or nitrogen; a(carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkylgroup; a (heteroaryl)alkyl group; or —C(O)NR_(m)R_(n); R_(m) and R_(n)are independently selected from the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkoxy, a C₆-C₁₀ aryl group; a 3- to6-membered heterocycloalkyl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen; a five- toten-membered heteroaryl ring containing one to four ring heteroatomsindependently selected from oxygen, sulfur, or nitrogen; a(carbocyclic)alkyl group; an aralkyl group; a (heterocycloalkyl)alkylgroup; or a (heteroaryl)alkyl group; and R₄ is optionally substitutedwith one to five R_(g) independently selected from the group consistingof hydroxy, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, C₁-C₆alkoxy, and C₆-C₁₀ aralkoxy; and R₅ is hydroxy, NH₂, alkylamino,alkanoylamino, or alkylsulfonylamino.
 180. The compound of claim 171, ora stereoisomer or a tautomer thereof, or a pharmaceutically acceptablesalt thereof, wherein: TL is a moiety of Formula IIId:


181. The compound of claim 171, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein: TL is a moietyof Formula IIa:


182. The compound of claim 181, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,—CN, C₁-C₆ alkyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or —C(O)—R_(j); wherein R_(j) is—NR_(m)R_(n) or —OR_(m); R_(m) is hydrogen or C₁-C₆ alkyl; R_(n) isC₁-C₆ alkyl; or R_(m) and R_(n), together with the nitrogen to whichthey are attached, form a ring structure; and R₁ is optionallysubstituted with one to three R_(k) independently selected from phenyland haloalkyl.
 183. The compound of claim 181, or a stereoisomer or atautomer thereof, or a pharmaceutically acceptable salt thereof, whereinR₂ is hydrogen; halogen; C₁-C₆ alkyl optionally substituted with one tofive substituents independently selected from the group consisting ofhydroxy, halogen, and C₁-C₆ alkoxy; C₃-C₉ cycloalkyl optionallysubstituted with one to ten substituents independently selected from thegroup consisting of hydroxy, halogen, and C₁-C₆ alkoxy; or —CN.
 184. Thecompound of claim 171, or a stereoisomer or a tautomer thereof, or apharmaceutically acceptable salt wherein: TL is a moiety of Formula IIb:


185. The compound of claim 171, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen;—CN; C₁-C₆ alkyl; a non-aromatic C₃-C₁₂ carbocyclic ring; a C₆-C₁₀ arylgroup; a 3- to 6-membered heterocycloalkyl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a five- to ten-membered heteroaryl ring containing one to fourring heteroatoms independently selected from oxygen, sulfur, ornitrogen; a (carbocyclic)alkyl group; an aralkyl group; a(heterocycloalkyl)alkyl group; or —C(O)—R_(j); wherein R_(j) is—NR_(m)R_(n) or —OR_(m); R_(m) is hydrogen or C₁-C₆ alkyl; R_(n) isC₁-C₆ alkyl; or R_(m) and R_(n), together with the nitrogen to whichthey are attached, form a ring structure; and R₁ is optionallysubstituted with one to five R_(k) independently selected from hydroxy,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, and C₆-C₁₀aralkoxy.
 186. The compound of claim 171, or a stereoisomer or atautomer thereof, or a pharmaceutically acceptable salt wherein: TL is amoiety of Formula IIIc:


187. The compound of claim 186, or a stereoisomer or a tautomer thereof,or a pharmaceutically acceptable salt thereof, wherein R₁₁ is a benzeneoptionally substituted with C₁-C₅ alkyl, halogen, or C₃-C₉ cycloalkyl;or naphthalene.
 188. The compound of claim 186, or a stereoisomer or atautomer thereof, or a pharmaceutically acceptable salt thereof, whereinR₅ is hydroxy, NH₂, C₁-C₆ alkylamino, C₁-C₆ alkanoylamino, or C₁-C₆alkylsulfonylamino.
 189. A compound selected from the group consistingof:

or a stereoisomer or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof.
 190. A pharmaceutical composition comprisingthe compound of claim 171, or the stereoisomer or the tautomer thereof,or the pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 191. A method of treating adisorder or disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of thecompound of claim 171, or the stereoisomer or the tautomer thereof, orthe pharmaceutically acceptable salt thereof, wherein the disorder ordisease is selected from non-alcoholic steatohepatitis (NASH), obesity,hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis,atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroidcancer.
 192. A method of treating a thyroid hormone receptor relateddisorder in a patient, the method comprising the steps of: identifying apatient in need of treatment for the thyroid hormone receptor relateddisorder, and administering to the patient, or contacting the patientwith, the compound of claim 171, or the stereoisomer or the tautomerthereof, or the pharmaceutically acceptable salt thereof.
 193. Themethod of claim 192, wherein the thyroid hormone receptor relateddisorder is selected from non-alcoholic steatohepatitis (NASH), obesity,hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis,atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroidcancer.
 194. A method of selectively modulating the activity of athyroid hormone receptor beta (THR-β) comprising contacting the compoundof claim 171, or the stereoisomer or the tautomer thereof, or thepharmaceutically acceptable salt thereof, with the thyroid hormonereceptor.